Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Tóm tắt
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.
Từ khóa
Tài liệu tham khảo
Pines, 2010, Oncogenic mutant forms of EGFR: Lessons in signal transduction and targets for cancer therapy, FEBS Lett., 584, 2699, 10.1016/j.febslet.2010.04.019
Cohen, 2004, Origins of growth factors: NGF and EGF, Ann. N. Y. Acad. Sci., 1038, 98, 10.1196/annals.1315.017
Cohen, 1962, Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal, J. Biol. Chem., 237, 1555, 10.1016/S0021-9258(19)83739-0
Cohen, 1965, The stimulation of epidermal proliferation by a specific protein (EGF), Dev. Biol., 12, 394, 10.1016/0012-1606(65)90005-9
Cohen, 1963, The stimulation of epidermal keratinization by a protein isolated from the submaxillary gland of the mouse, J. Investig. Dermatol., 40, 1, 10.1038/jid.1963.1
Cohen, 1980, Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity, J. Biol. Chem., 255, 4834, 10.1016/S0021-9258(19)85573-4
Cohen, 1982, A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles, J. Biol. Chem., 257, 1523, 10.1016/S0021-9258(19)68224-4
Carpenter, 1975, Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts, J. Biol. Chem., 250, 4297, 10.1016/S0021-9258(19)41417-8
Ushiro, 1980, Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes, J. Biol. Chem., 255, 8363, 10.1016/S0021-9258(18)43497-7
Downward, 1984, Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences, Nature, 307, 521, 10.1038/307521a0
Ullrich, 1984, Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells, Nature, 309, 418, 10.1038/309418a0
Olofsson, 1986, Structure and expression of the chicken epidermal growth factor receptor gene locus, Eur. J. Biochem., 160, 261, 10.1111/j.1432-1033.1986.tb09965.x
Gusterson, 1984, Cellular localisation of human epidermal growth factor receptor, Cell Biol. Int. Rep., 8, 649, 10.1016/0309-1651(84)90045-6
Cowley, 1986, Increased EGF receptors on human squamous carcinoma cell lines, Br. J. Cancer, 53, 223, 10.1038/bjc.1986.39
Gusterson, 1985, Evidence for increased epidermal growth factor receptors in human sarcomas, Int. J. Cancer, 36, 689, 10.1002/ijc.2910360612
Veale, 1987, Epidermal growth factor receptors in non-small cell lung cancer, Br. J. Cancer, 55, 513, 10.1038/bjc.1987.104
Wong, 1987, Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification, Proc. Natl. Acad. Sci. USA, 84, 6899, 10.1073/pnas.84.19.6899
Slamon, 1987, Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene, Science, 235, 177, 10.1126/science.3798106
Richard, 1987, Epidermal-growth-factor receptor status as predictor of early recurrence of and death from breast cancer, Lancet, 329, 1398, 10.1016/S0140-6736(87)90593-9
Velu, 1987, Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene, Science, 238, 1408, 10.1126/science.3500513
Pierce, 1987, Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells, Cell, 51, 1063, 10.1016/0092-8674(87)90592-7
Lemmon, 2010, Cell signaling by receptor tyrosine kinases, Cell, 141, 1117, 10.1016/j.cell.2010.06.011
Tzahar, 1996, A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor, Mol. Cell. Biol., 16, 5276, 10.1128/MCB.16.10.5276
Beerli, 1997, ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling, EMBO J., 16, 1647, 10.1093/emboj/16.7.1647
Holbro, 2003, The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation, Proc. Natl. Acad. Sci. USA, 100, 8933, 10.1073/pnas.1537685100
Burgess, 2003, An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors, Mol. Cell, 12, 541, 10.1016/S1097-2765(03)00350-2
Tomas, 2014, EGF receptor trafficking: Consequences for signaling and cancer, Trends Cell Biol., 24, 26, 10.1016/j.tcb.2013.11.002
Aroian, 1990, The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily, Nature, 348, 693, 10.1038/348693a0
Wasserman, 1997, Control of EGF receptor activation in Drosophila, Trends Cell Biol., 7, 431, 10.1016/S0962-8924(97)01143-4
Lusk, J., Lam, V., and Tolwinski, N. (2017). Epidermal Growth Factor Pathway Signaling in Drosophila Embryogenesis: Tools for Understanding Cancer. Cancers, 9.
Davies, 1980, Genetic analysis of epidermal growth factor action: Assignment of human epidermal growth factor receptor gene to chromosome 7, Proc. Natl. Acad. Sci. USA, 77, 4188, 10.1073/pnas.77.7.4188
Kondo, 1983, Mapping of the human gene for epidermal growth factor receptor (EGFR) on the p13 leads to q22 region of chromosome 7, Cytogenet. Cell Genet., 35, 9, 10.1159/000131829
Carpenter, 1979, Epidermal growth factor, Annu. Rev. Biochem., 48, 193, 10.1146/annurev.bi.48.070179.001205
Gullick, 1986, Expression of Epidermal Growth Factor Receptors on Human Cervical, Ovarian, and Vulval Carcinomas, Cancer Res., 46, 285
Clark, 1985, Epidermal growth factor regulates the expression of its own receptor, Proc. Natl. Acad. Sci. USA, 82, 8374, 10.1073/pnas.82.24.8374
Kageyama, 1988, A transcription factor active on the epidermal growth factor receptor gene, Proc. Natl. Acad. Sci. USA, 85, 5016, 10.1073/pnas.85.14.5016
Haley, 1987, The human EGF receptor gene: Structure of the 110 kb locus and identification of sequences regulating its transcription, Oncogene Res., 1, 375
Johnson, 1988, Epidermal growth factor receptor gene promoter, J. Biol. Chem., 263, 5693, 10.1016/S0021-9258(18)60621-0
Johnson, 1996, Activation of epidermal growth factor receptor gene transcription by phorbol 12-myristate 13-acetate is mediated by activator protein 2, J. Biol. Chem., 271, 3033, 10.1016/S0021-9258(18)97974-3
Mialon, 2005, DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation, Mol. Cell. Biol., 25, 5040, 10.1128/MCB.25.12.5040-5051.2005
Fisher, 1990, Metabolism and effects of epidermal growth factor and related growth factors in mammals, Endocr. Rev., 11, 418, 10.1210/edrv-11-3-418
Chia, 1995, EGF, TGF-alpha and EGFR expression in human preimplantation embryos, Development, 121, 299, 10.1242/dev.121.2.299
Roskoski, 2014, The ErbB/HER family of protein-tyrosine kinases and cancer, Pharmacol. Res., 79, 34, 10.1016/j.phrs.2013.11.002
Olayioye, 2000, The ErbB signaling network: Receptor heterodimerization in development and cancer, EMBO J., 19, 3159, 10.1093/emboj/19.13.3159
Campbell, 1993, Epidermal growth factor-like modules, Curr. Opin. Struct. Biol., 3, 385, 10.1016/S0959-440X(05)80111-3
Threadgill, 1995, Targeted disruption of mouse EGF receptor: Effect of genetic background on mutant phenotype, Science, 269, 230, 10.1126/science.7618084
Lee, 1995, Requirement for neuregulin receptor erbB2 in neural and cardiac development, Nature, 378, 394, 10.1038/378394a0
Morris, 1999, Rescue of the cardiac defect in erbB2 mutant mice reveals essential roles of erbB2 in peripheral nervous system development, Neuron, 23, 273, 10.1016/S0896-6273(00)80779-5
Lin, 2000, Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice, Proc. Natl. Acad. Sci. USA, 97, 1299, 10.1073/pnas.97.3.1299
Erickson, 1997, ErbB3 is required for normal cerebellar and cardiac development: A comparison with ErbB2-and heregulin-deficient mice, Development, 124, 4999, 10.1242/dev.124.24.4999
Riethmacher, 1997, Severe neuropathies in mice with targeted mutations in the ErbB3 receptor, Nature, 389, 725, 10.1038/39593
Golding, 2000, Defects in pathfinding by cranial neural crest cells in mice lacking the Neuregulin receptor ErbB4, Nat. Cell Biol., 2, 103, 10.1038/35000058
Jones, 2003, ErbB4 signaling during breast and neural development: Novel genetic models reveal unique ErbB4 activities, Cell Cycle, 2, 555, 10.4161/cc.2.6.598
Gassmann, 1995, Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor, Nature, 378, 390, 10.1038/378390a0
Green, 1983, Distribution and number of epidermal growth factor receptors in skin is related to epithelial cell growth, Dev. Biol., 100, 506, 10.1016/0012-1606(83)90243-9
Zieske, 1993, Regional variation in distribution of EGF receptor in developing and adult corneal epithelium, J. Cell Sci., 106, 145, 10.1242/jcs.106.1.145
Fowler, 1995, A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation, Proc. Natl. Acad. Sci. USA, 92, 1465, 10.1073/pnas.92.5.1465
Xie, 1997, Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development, Mol. Endocrinol., 11, 1766, 10.1210/mend.11.12.0019
Wiesen, 1999, Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development, Development, 126, 335, 10.1242/dev.126.2.335
Yamada, 1997, The neurotrophic action and signalling of epidermal growth factor, Prog. Neurobiol., 51, 19, 10.1016/S0301-0082(96)00046-9
Liu, 2007, Activation of epidermal growth factor receptors in astrocytes: From development to neural injury, J. Neurosci. Res., 85, 3523, 10.1002/jnr.21364
Knauer, 1988, Epidermal growth factor receptor immunoreactivity in rat brain. Development and cellular localization, Brain Res., 438, 385, 10.1016/0006-8993(88)91369-8
Ciccolini, 2005, Prospective isolation of late development multipotent precursors whose migration is promoted by EGFR, Dev. Biol., 284, 112, 10.1016/j.ydbio.2005.05.007
Knauer, 1988, Epidermal growth factor receptor immunoreactivity in rat brain astrocytes. Response to injury, Neurosci. Lett., 91, 276, 10.1016/0304-3940(88)90693-3
Carpenter, 1991, Structural analysis of the transmembrane domain of the epidermal growth factor receptor, J. Biol. Chem., 266, 5750, 10.1016/S0021-9258(19)67659-3
Morrow, 2000, The EGF receptor transmembrane domain: Peptide-peptide interactions in fluid bilayer membranes, Biophys. J., 79, 2024, 10.1016/S0006-3495(00)76450-2
Cymer, 2010, Transmembrane helix-helix interactions involved in ErbB receptor signaling, Cell Adhes. Migr., 4, 299, 10.4161/cam.4.2.11191
Tanner, 1999, Dimerization of the extracellular domain of the receptor for epidermal growth factor containing the membrane-spanning segment in response to treatment with epidermal growth factor, J. Biol. Chem., 274, 35985, 10.1074/jbc.274.50.35985
Bell, 2000, Rotational coupling of the transmembrane and kinase domains of the Neu receptor tyrosine kinase, Mol. Biol Cell, 11, 3589, 10.1091/mbc.11.10.3589
Walton, 1990, Analysis of deletions of the carboxyl terminus of the epidermal growth factor receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates, J. Biol. Chem., 265, 1750, 10.1016/S0021-9258(19)40080-X
Stamos, 2002, Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor, J. Biol. Chem., 277, 46265, 10.1074/jbc.M207135200
Zhang, 2006, An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor, Cell, 125, 1137, 10.1016/j.cell.2006.05.013
Lee, J.C., Vivanco, I., Beroukhim, R., Huang, J.H.Y., Feng, W.L., DeBiasi, R.M., Yoshimoto, K., King, J.C., Nghiemphu, P., and Yuza, Y. (2006). Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med., 3.
Barber, 2004, Somatic Mutations of EGFR in Colorectal Cancers and Glioblastomas, N. Engl. J. Med., 351, 2883, 10.1056/NEJM200412303512724
Cappuzzo, 2008, EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients, Ann. Oncol., 19, 717, 10.1093/annonc/mdm492
Fujino, 1996, A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer, Eur. J. Cancer, 32, 2070, 10.1016/S0959-8049(96)00243-2
Endres, 2014, Emerging concepts in the regulation of the EGF receptor and other receptor tyrosine kinases, Trends Biochem. Sci., 39, 437, 10.1016/j.tibs.2014.08.001
Yun, 2013, Mechanism for activation of mutated epidermal growth factor receptors in lung cancer, Proc. Natl. Acad. Sci. USA, 110, E3595
Gan, 2013, The epidermal growth factor receptor variant III (EGFRvIII): Where wild things are altered, FEBS J., 280, 5350, 10.1111/febs.12393
Schmidt, 2003, Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization, Proc. Natl. Acad. Sci. USA, 100, 6505, 10.1073/pnas.1031790100
Paez, 2004, EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy, Science, 304, 1497, 10.1126/science.1099314
Shigematsu, 2005, Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers, J. Natl. Cancer Inst., 97, 339, 10.1093/jnci/dji055
Carey, 2006, Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, Cancer Res., 66, 8163, 10.1158/0008-5472.CAN-06-0453
Yun, 2007, Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity, Cancer Cell, 11, 217, 10.1016/j.ccr.2006.12.017
Kumar, 2008, Structure and clinical relevance of the epidermal growth factor receptor in human cancer, J. Clin. Oncol., 26, 1742, 10.1200/JCO.2007.12.1178
Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci. Transl. Med., 5, 216ra177, 10.1126/scitranslmed.3007205
Zhang, 2010, EGFR-mutated lung cancer: A paradigm of molecular oncology, Oncotarget, 1, 497, 10.18632/oncotarget.186
Yun, 2008, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Proc. Natl. Acad. Sci. USA, 105, 2070, 10.1073/pnas.0709662105
Inukai, 2006, Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer, Cancer Res., 66, 7854, 10.1158/0008-5472.CAN-06-1951
Olsen, 2006, Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks, Cell, 127, 635, 10.1016/j.cell.2006.09.026
Waters, K.M., Liu, T., Quesenberry, R.D., Willse, A.R., Bandyopadhyay, S., Kathmann, L.E., Weber, T.J., Smith, R.D., Wiley, H.S., and Thrall, B.D. (2012). Network analysis of epidermal growth factor signaling using integrated genomic, proteomic and phosphorylation data. PLoS ONE, 7.
Oda, 2005, A comprehensive pathway map of epidermal growth factor receptor signaling, Mol. Syst. Biol., 1, 2005.0010, 10.1038/msb4100014
Conte, A., and Sigismund, S. (2016). The Ubiquitin Network in the Control of EGFR Endocytosis and Signaling. Prog. Mol. Biol. Transl. Sci.
Sigismund, 2005, Clathrin-independent endocytosis of ubiquitinated cargos, Proc. Natl. Acad. Sci. USA, 102, 2760, 10.1073/pnas.0409817102
Kasselberg, 1985, Immunocytochemical localization of human epidermal growth factor/urogastrone in several human tissues, J. Histochem. Cytochem., 33, 315, 10.1177/33.4.3884705
Edwin, 2006, A historical perspective of the EGF receptor and related systems, Methods Mol. Biol., 327, 1
Singh, 2005, Autocrine, paracrine and juxtacrine signaling by EGFR ligands, Cell Signal., 17, 1183, 10.1016/j.cellsig.2005.03.026
Singh, 2016, EGF receptor ligands: Recent advances, F1000Research, 5, 2270, 10.12688/f1000research.9025.1
Normanno, 2006, Epidermal growth factor receptor (EGFR) signaling in cancer, Gene, 366, 2, 10.1016/j.gene.2005.10.018
Carraway, 1997, Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases, Nature, 387, 512, 10.1038/387512a0
Chang, 1997, Ligands for ErbB-family receptors encoded by a neuregulin-like gene, Nature, 387, 509, 10.1038/387509a0
Wheeler, 2010, Understanding resistance to EGFR inhibitors-impact on future treatment strategies, Nat. Rev. Clin. Oncol., 7, 493, 10.1038/nrclinonc.2010.97
Zhang, 1997, Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4, Proc. Natl. Acad. Sci. USA, 94, 9562, 10.1073/pnas.94.18.9562
Roepstorff, 2009, Differential effects of EGFR ligands on endocytic sorting of the receptor, Traffic, 10, 1115, 10.1111/j.1600-0854.2009.00943.x
Sweeney, 2001, Growth Factor-specific Signaling Pathway Stimulation and Gene Expression Mediated by ErbB Receptors, J. Biol. Chem., 276, 22685, 10.1074/jbc.M100602200
Ebner, 1991, Epidermal growth factor and transforming growth factor-alpha: Differential intracellular routing and processing of ligand-receptor complexes, Cell Regul., 2, 599, 10.1091/mbc.2.8.599
French, 1995, Intracellular trafficking of epidermal growth factor family ligands is directly influenced by the pH sensitivity of the receptor/ligand interaction, J. Biol. Chem., 270, 4334, 10.1074/jbc.270.9.4334
Waterman, 1998, Alternative intracellular routing of ErbB receptors may determine signaling potency, J. Biol. Chem., 273, 13819, 10.1074/jbc.273.22.13819
Wilson, 2009, Functional selectivity of EGF family peptide growth factors: Implications for cancer, Pharmacol. Ther., 122, 1, 10.1016/j.pharmthera.2008.11.008
Todaro, 1978, Growth factors from murine sarcoma virus-transformed cells, Proc. Natl. Acad. Sci. USA, 75, 4001, 10.1073/pnas.75.8.4001
Yarden, 1987, Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor, Biochemistry, 26, 1443, 10.1021/bi00379a035
Yarden, 1987, Self-phosphorylation of epidermal growth factor receptor: Evidence for a model of intermolecular allosteric activation, Biochemistry, 26, 1434, 10.1021/bi00379a034
Ferguson, 2003, EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization, Mol. Cell, 11, 507, 10.1016/S1097-2765(03)00047-9
Jura, 2009, Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment, Cell, 137, 1293, 10.1016/j.cell.2009.04.025
Clayton, 2005, Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor-A multidimensional microscopy analysis, J. Biol. Chem., 280, 30392, 10.1074/jbc.M504770200
Gadella, 1995, Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation, J. Cell Biol., 129, 1543, 10.1083/jcb.129.6.1543
Tao, 2008, All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells, J. Cell Sci., 121, 3207, 10.1242/jcs.033399
Chung, 2010, Spatial control of EGF receptor activation by reversible dimerization on living cells, Nature, 464, 783, 10.1038/nature08827
Bessman, 2014, Complex Relationship between Ligand Binding and Dimerization in the Epidermal Growth Factor Receptor, Cell Rep., 9, 1306, 10.1016/j.celrep.2014.10.010
Lu, 2012, Mechanisms for kinase-mediated dimerization of the epidermal growth factor receptor, J. Biol. Chem., 287, 38244, 10.1074/jbc.M112.414391
Li, 2010, Receptor tyrosine kinase transmembrane domains: Function, dimer structure and dimerization energetics, Cell Adhes. Migr., 4, 249, 10.4161/cam.4.2.10725
Sato, 2013, Cellular Functions Regulated by Phosphorylation of EGFR on Tyr845, Int. J. Mol. Sci., 14, 10761, 10.3390/ijms140610761
Hunter, 1984, Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane, Nature, 311, 480, 10.1038/311480a0
Pawson, 2004, Specificity in Signal Transduction: From Phosphotyrosine-SH2 Domain Interactions to Complex Cellular Systems, Cell, 116, 191, 10.1016/S0092-8674(03)01077-8
Morrison, 2012, MAP Kinase Pathways, Cold Spring Harb. Perspect. Biol., 4, a011254, 10.1101/cshperspect.a011254
Lewis, 1998, Signal Transduction through MAP Kinase Cascades, Adv. Cancer Res., 74, 49, 10.1016/S0065-230X(08)60765-4
Lowenstein, 1992, The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling, Cell, 70, 431, 10.1016/0092-8674(92)90167-B
Buday, 1993, Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor, Cell, 73, 611, 10.1016/0092-8674(93)90146-H
Jiang, 2003, Grb2 regulates internalization of EGF receptors through clathrin-coated pits, Mol. Biol Cell, 14, 858, 10.1091/mbc.e02-08-0532
Batzer, 1994, Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor, Mol. Cell. Biol., 14, 5192
Pelicci, 1992, A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction, Cell, 70, 93, 10.1016/0092-8674(92)90536-L
Okabayashi, 1994, Tyrosines 1148 and 1173 of activated human epidermal growth factor receptors are binding sites of Shc in intact cells, J. Biol. Chem., 269, 18674, 10.1016/S0021-9258(17)32363-3
Sakaguchi, 1998, Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells, Mol. Endocrinol., 12, 536, 10.1210/mend.12.4.0094
Salcini, 1994, Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins, Oncogene, 9, 2827
Wiley, 1995, A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides, Curr. Biol., 5, 404, 10.1016/S0960-9822(95)00081-9
Chardin, 1993, Human Sos1: A guanine nucleotide exchange factor for Ras that binds to GRB2, Science, 260, 1338, 10.1126/science.8493579
Li, 1993, Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling, Nature, 363, 85, 10.1038/363085a0
Egan, 1993, Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation, Nature, 363, 45, 10.1038/363045a0
Fernley, 1993, The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1, Nature, 363, 83, 10.1038/363083a0
Simon, 1995, Grb2 SH3 binding to peptides from Sos: Evaluation of a general model for SH3-ligand interactions, Chem. Biol., 2, 53, 10.1016/1074-5521(95)90080-2
Margarit, 1998, The structural basis of the activation of Ras by Sos, Nature, 394, 337, 10.1038/28548
Brtva, 1995, Two distinct Raf domains mediate interaction with Ras, J. Biol. Chem., 270, 9809, 10.1074/jbc.270.17.9809
Xiang, 2002, Phosphorylation of 338SSYY341 regulates specific interaction between Raf-1 and MEK1, J. Biol. Chem., 277, 44996, 10.1074/jbc.M203953200
Zang, 2008, Characterization of Ser338 phosphorylation for Raf-1 activation, J. Biol. Chem., 283, 31429, 10.1074/jbc.M802855200
Diaz, 1997, Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling, Mol. Cell. Biol., 17, 4509, 10.1128/MCB.17.8.4509
Fabian, 1993, Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase, Mol. Cell. Biol., 13, 7170
Bondzi, 2000, A novel assay for the measurement of Raf-1 kinase activity, Oncogene, 19, 5030, 10.1038/sj.onc.1203862
Dhanasekaran, 1998, Signaling by dual specificity kinases, Oncogene, 17, 1447, 10.1038/sj.onc.1202251
Sasaoka, 1994, The Signaling Pathway Coupling Epidermal Growth Factor Receptors to Activation of p21ras, J. Biol. Chem., 269, 32621, 10.1016/S0021-9258(18)31679-X
Lanzerstorfer, P., Borgmann, D., Schütz, G., Winkler, S.M., Höglinger, O., and Weghuber, J. (2014). Quantification and kinetic analysis of Grb2-EGFR interaction on micro-patterned surfaces for the characterization of EGFR-modulating substances. PLoS ONE, 9.
Lee, 2006, The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis, Nat. Cell Biol., 8, 477, 10.1038/ncb1401
Zhao, 2007, Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos, Nat. Cell Biol., 9, 706, 10.1038/ncb1594
Soubeyran, 2002, Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors, Nature, 416, 183, 10.1038/416183a
Waterman, 2002, A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling, EMBO J., 21, 303, 10.1093/emboj/21.3.303
Fukazawa, 1996, Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation and its association with EGF receptor and downstream signaling proteins, J. Biol. Chem., 271, 14554, 10.1074/jbc.271.24.14554
Sigismund, 2013, Threshold-controlled ubiquitination of the EGFR directs receptor fate, EMBO J., 32, 2140, 10.1038/emboj.2013.149
Gureasko, 2008, Membrane-dependent signal integration by the Ras activator Son of sevenless, Nat. Struct. Mol. Biol., 15, 452, 10.1038/nsmb.1418
Kim, 2000, Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-γ1, Biochemistry, 39, 8674, 10.1021/bi992558t
Maertens, 2014, An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer, Adv. Biol. Regul., 55, 1, 10.1016/j.jbior.2014.04.002
Bunda, 2014, Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation, Proc. Natl. Acad. Sci. USA, 111, E3785, 10.1073/pnas.1406559111
Bunda, 2015, Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis, Nat. Commun., 6, 8859, 10.1038/ncomms9859
Kano, 2016, New structural and functional insight into the regulation of Ras, Semin. Cell Dev. Biol., 58, 70, 10.1016/j.semcdb.2016.06.006
Findlay, 2008, How is SOS activated? Let us count the ways, Nat. Struct. Mol. Biol., 15, 538, 10.1038/nsmb0608-538
Hofer, 1994, Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator, Proc. Natl. Acad. Sci. USA, 91, 11089, 10.1073/pnas.91.23.11089
Warne, 1994, Phosphatidylinositol-3-OH kinase as a direct target of Ras, Nature, 370, 527, 10.1038/370527a0
Santos, 2011, Ras in cancer and developmental diseases, Genes Cancer, 2, 344, 10.1177/1947601911411084
Hallberg, 1994, Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation, J. Biol. Chem., 269, 3913, 10.1016/S0021-9258(17)41718-2
Niederst, 2013, Suppression of survival signalling pathways by the phosphatase PHLPP, FEBS J., 280, 572, 10.1111/j.1742-4658.2012.08537.x
Untch, 2015, NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition, Cancer Discov., 5, 1178, 10.1158/2159-8290.CD-15-0330
Hu, 1995, Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras, J. Biol. Chem., 270, 30274, 10.1074/jbc.270.51.30274
Hu, 1997, Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with Ras-dependent activation of Raf-1, J. Biol. Chem., 272, 11702, 10.1074/jbc.272.18.11702
Luo, 1997, An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ, Mol. Cell. Biol., 17, 46, 10.1128/MCB.17.1.46
Roy, 1997, Activity of plasma membrane-recruited Raf-1 is regulated by Ras via the Raf zinc finger, J. Biol. Chem., 272, 20139, 10.1074/jbc.272.32.20139
Dhillon, 2002, Untying the regulation of the Raf-1 kinase, Arch. Biochem. Biophys., 404, 3, 10.1016/S0003-9861(02)00244-8
Garnett, 2004, Guilty as charged: B-RAF is a human oncogene, Cancer Cell, 6, 313, 10.1016/j.ccr.2004.09.022
Marais, 1996, Control of the ERK MAP kinase cascade by Ras and Raf, Cancer Surv., 27, 101
Mason, 1999, Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation, EMBO J., 18, 2137, 10.1093/emboj/18.8.2137
King, 1998, The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338, Nature, 396, 180, 10.1038/24184
Chiloeches, 2001, S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3, Mol. Cell. Biol., 21, 2423, 10.1128/MCB.21.7.2423-2434.2001
Frost, 1997, Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins, EMBO J., 16, 6426, 10.1093/emboj/16.21.6426
Eblen, 2003, PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation, J. Cell Biol., 162, 281, 10.1083/jcb.200212141
Chaudhary, 2000, Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine 338, Curr. Biol., 10, 551, 10.1016/S0960-9822(00)00475-9
Zhu, 2005, Identification of Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities and for MEK binding, Mol. Biol Cell, 16, 4733, 10.1091/mbc.e05-02-0090
Chong, 2001, Positive and negative regulation of Raf kinase activity and function by phosphorylation, EMBO J., 20, 3716, 10.1093/emboj/20.14.3716
Michaud, 1995, 14-3-3 is not essential for Raf-1 function: Identification of Raf-1 proteins that are biologically activated in a 14-3-3- and Ras-independent manner, Mol. Cell. Biol., 15, 3390, 10.1128/MCB.15.6.3390
Muslin, 1996, Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine, Cell, 84, 889, 10.1016/S0092-8674(00)81067-3
Zimmermann, 1999, Phosphorylation and regulation of Raf by Akt (protein kinase B), Science, 286, 1741, 10.1126/science.286.5445.1741
Roy, 1998, 14-3-3 Facilitates Ras-Dependent Raf-1 Activation In Vitro and In Vivo 14-3-3 Facilitates Ras-Dependent Raf-1 Activation In Vitro and In Vivo, Mol. Cell. Biol., 18, 3947, 10.1128/MCB.18.7.3947
Rommel, 1996, Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1, Oncogene, 12, 609
Kubicek, 2002, Dephosphorylation of Ser-259 regulates Raf-1 membrane association, J. Biol. Chem., 277, 7913, 10.1074/jbc.M108733200
Abraham, 2000, Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation, J. Biol. Chem., 275, 22300, 10.1074/jbc.M003259200
Tzivion, 1998, A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity, Nature, 394, 88, 10.1038/27938
Mischak, 1996, Negative regulation of Raf-1 by phosphorylation of serine 621, Mol. Cell. Biol., 16, 5409, 10.1128/MCB.16.10.5409
Thorson, 1998, 14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity, Mol. Cell. Biol., 18, 5229, 10.1128/MCB.18.9.5229
Dougherty, 2005, Regulation of Raf-1 by direct feedback phosphorylation, Mol. Cell, 17, 215, 10.1016/j.molcel.2004.11.055
Rushworth, 2006, Regulation and Role of Raf-1 / B-Raf Heterodimerization, Mol. Cell. Biol., 26, 2262, 10.1128/MCB.26.6.2262-2272.2006
Roskoski, 2012, ERK1/2 MAP kinases: Structure, function, and regulation, Pharmacol. Res., 66, 105, 10.1016/j.phrs.2012.04.005
Fujioka, 2006, Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes, J. Biol. Chem., 281, 8917, 10.1074/jbc.M509344200
Roberts, 2007, Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer, Oncogene, 26, 3291, 10.1038/sj.onc.1210422
Brunet, 1994, Constitutively active mutants of MAP kinase kinase (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts, Oncogene, 9, 3379
Cowley, 1994, Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells, Cell, 77, 841, 10.1016/0092-8674(94)90133-3
Lefloch, 2009, Total ERK1/2 activity regulates cell proliferation, Cell Cycle, 8, 705, 10.4161/cc.8.5.7734
Yoon, 2006, The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions, Growth Factors, 24, 21, 10.1080/02699050500284218
Richards, 2001, Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1, Mol. Cell. Biol., 21, 7470, 10.1128/MCB.21.21.7470-7480.2001
Dalby, 1998, Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90(rsk) that are inducible by MAPK, J. Biol. Chem., 273, 1496, 10.1074/jbc.273.3.1496
Jensen, 1999, 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3- phosphoinositide-dependent protein kinase-1, J. Biol. Chem., 274, 27168, 10.1074/jbc.274.38.27168
Anjum, 2008, The RSK family of kinases: Emerging roles in cellular signalling, Nat. Rev. Mol. Cell. Biol., 9, 747, 10.1038/nrm2509
Murphy, 2006, MAPK signal specificity: The right place at the right time, Trends Biochem Sci, 31, 268, 10.1016/j.tibs.2006.03.009
Stacey, 1987, Microinjection of transforming ras protein induces c-fos expression, Mol. Cell. Biol., 7, 523
Quantin, 1988, Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts, Nature, 334, 538, 10.1038/334538a0
Hollenhorst, 2011, Genomic and biochemical insights into the specificity of ETS transcription factors, Annu. Rev. Biochem., 80, 437, 10.1146/annurev.biochem.79.081507.103945
Buchwalter, 2004, Ets ternary complex transcription factors, Gene, 324, 1, 10.1016/j.gene.2003.09.028
Herber, 1994, Inducible regulatory elements in the human Cyclin D1 promoter, Oncogene, 9, 1295
Albanese, 1995, Transforming p21(ras) mutants and c-Ets-2 activate the Cyclin D1 promoter through distinguishable regions, J. Biol. Chem., 270, 23589, 10.1074/jbc.270.40.23589
Okazaki, 1995, The Mos/MAP kinase pathway stabilizes c-fos by phosphorylation and augments its transforming activity in NIH 3T3 cells, EMBO J., 14, 5048, 10.1002/j.1460-2075.1995.tb00187.x
Morton, 2003, A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun, EMBO J., 22, 3876, 10.1093/emboj/cdg388
Jin, 2014, FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer, Ann. Surg. Oncol., 21, S758, 10.1245/s10434-014-3980-3
Berry, 2006, Regulation of FOXC1 stability and transcriptional activity by an epidermal growth factor-activated mitogen-activated protein kinase signaling cascade, J. Biol. Chem., 281, 10098, 10.1074/jbc.M513629200
Chambard, 2007, ERK implication in cell cycle regulation, Biochim. Biophys. Acta Mol. Cell Res, 1773, 1299, 10.1016/j.bbamcr.2006.11.010
Dibble, 2015, Regulation of mTORC1 by PI3K signaling, Trends Cell Biol., 25, 545, 10.1016/j.tcb.2015.06.002
Whitman, 1988, Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate, Nature, 332, 644, 10.1038/332644a0
Bjorge, 1990, Activated type I phosphatidylinositol kinase is associated with the epidermal growth factor (EGF) receptor following EGF stimulation, Proc. Natl. Acad. Sci. USA, 87, 3816, 10.1073/pnas.87.10.3816
Thorpe, 2015, PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting, Nat. Rev. Cancer, 15, 7, 10.1038/nrc3860
Fruman, 2002, Phosphoinositide 3-kinase in immunological systems, Semin. Immunol., 14, 7, 10.1006/smim.2001.0337
Auger, 1989, PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells, Cell, 57, 167, 10.1016/0092-8674(89)90182-7
Carpenter, 1990, Purification and characterization of phosphoinositide 3-kinase from rat liver, J. Biol. Chem., 265, 19704, 10.1016/S0021-9258(17)45429-9
Vogt, 2010, Phosphatidylinositol 3-kinase: The oncoprotein, Curr. Top. Microbiol. Immunol., 347, 79
Vanhaesebroeck, 2012, PI3K signalling: The path to discovery and understanding, Nat. Rev. Mol. Cell. Biol., 13, 195, 10.1038/nrm3290
Soltoff, 1994, ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor, Mol. Cell. Biol., 14, 3550
Kim, 1994, Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product, J. Biol. Chem., 269, 24747, 10.1016/S0021-9258(17)31455-2
Soltoff, 1996, p120cbl is a cytosolic adapter protein that associates with phosphoinositide 3-kinase in response to epidermal growth factor in PC12 and other cells, J. Biol. Chem., 271, 563, 10.1074/jbc.271.1.563
Mattoon, D.R., Lamothe, B., Lax, I., and Schlessinger, J. (2004). The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway. BMC Biol., 2.
Lock, 2000, Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyorosine kinases, J. Biol. Chem., 275, 31536, 10.1074/jbc.M003597200
Maroun, 1999, The Gab1 PH domain is required for localization of Gab1 at sites of cell-cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase, Mol. Cell. Biol., 19, 1784, 10.1128/MCB.19.3.1784
Yamamoto, 1991, Association of p21ras with phosphatidylinositol 3-kinase, Proc. Natl. Acad. Sci. USA, 88, 7908, 10.1073/pnas.88.18.7908
Warne, 1996, Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation, EMBO J., 15, 2442, 10.1002/j.1460-2075.1996.tb00602.x
Cuevas, 2001, Tyrosine Phosphorylation of p85 Relieves Its Inhibitory Activity on Phosphatidylinositol 3-Kinase, J. Biol. Chem., 276, 27455, 10.1074/jbc.M100556200
Franke, 1997, Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate, Science, 275, 665, 10.1126/science.275.5300.665
Chan, 2012, The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis, Cell, 149, 1098, 10.1016/j.cell.2012.02.065
Toker, 2000, Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site, J. Biol. Chem., 275, 8271, 10.1074/jbc.275.12.8271
Pearce, 2010, The nuts and bolts of AGC protein kinases, Nat. Rev. Mol. Cell. Biol., 11, 9, 10.1038/nrm2822
Stephens, 1998, Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B, Science, 279, 710, 10.1126/science.279.5351.710
Casamayor, 1999, Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: Identification of five sites of phosphorylation in vivo, Biochem. J., 342, 287, 10.1042/bj3420287
Sarbassov, 2005, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science, 307, 1098, 10.1126/science.1106148
Gao, 2005, PHLPP: A phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth, Mol. Cell, 18, 13, 10.1016/j.molcel.2005.03.008
Brognard, 2007, PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms, Mol. Cell, 25, 917, 10.1016/j.molcel.2007.02.017
Jakubowicz, 1996, Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors, Proc. Natl. Acad. Sci. USA, 93, 5699, 10.1073/pnas.93.12.5699
Santi, 2010, The Akt isoforms are present at distinct subcellular locations, Am. J. Physiol. Cell Physiol., 298, C580, 10.1152/ajpcell.00375.2009
Yang, 2003, Protein kinase Bα/Akt1 regulates placental development and fetal growth, J. Biol. Chem., 278, 32124, 10.1074/jbc.M302847200
Zinda, 2001, AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon, Clin. Cancer Res., 7, 2475
Lobo, 2013, Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells, Cell Signal., 25, 1586, 10.1016/j.cellsig.2013.03.019
Cho, 2001, Akt1/PKBalpha Is Required for Normal Growth but Dispensable for Maintenance of Glucose Homeostasis in Mice, J. Biol. Chem., 276, 38349, 10.1074/jbc.C100462200
Dummler, 2006, Life with a single isoform of Akt: Mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies, Mol. Cell. Biol., 26, 8042, 10.1128/MCB.00722-06
Garofalo, 2003, Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB??, J. Clin. Investig., 112, 197, 10.1172/JCI16885
Arboleda, 2003, Overexpression of AKT2/protein kinase B beta leads to up- regulation of beta 1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells, Cancer Res., 63, 196
Irie, 2005, Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition, J. Cell Boil., 17, 1023, 10.1083/jcb.200505087
Ju, 2007, Akt1 governs breast cancer progression in vivo, Proc. Natl. Acad. Sci. USA, 104, 7438, 10.1073/pnas.0605874104
Lee, 2011, Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration, Cancer Sci., 102, 1822, 10.1111/j.1349-7006.2011.02025.x
Franckhauser, 2006, Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding, Mol. Cell. Biol., 26, 8267, 10.1128/MCB.00201-06
Linnerth-Petrik, N.M., Santry, L.A., Petrik, J.J., and Wootton, S.K. (2014). Opposing functions of Akt isoforms in lung tumor initiation and progression. PLoS ONE, 9.
Akerberg, 2003, Akt kinases in breast cancer and the results of adjuvant therapy, Breast Cancer Res., 5, R37, 10.1186/bcr569
Staal, 1987, Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: Amplification of AKT1 in a primary human gastric adenocarcinoma, Proc. Natl. Acad. Sci. USA, 84, 5034, 10.1073/pnas.84.14.5034
Carpten, 2007, A transforming mutation in the pleckstrin homology domain of AKT1 in cancer, Nature, 448, 439, 10.1038/nature05933
Chen, 2006, The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/− mice, Genes Dev., 20, 1569, 10.1101/gad.1395006
Cheng, 1996, Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA, Proc. Natl. Acad. Sci. USA, 93, 3636, 10.1073/pnas.93.8.3636
Cheng, 1992, AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas, Proc. Natl. Acad. Sci. USA, 89, 9267, 10.1073/pnas.89.19.9267
Roy, 2002, AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis, Carcinogenesis, 23, 201, 10.1093/carcin/23.1.201
Xu, 2004, Akt2 expression correlates with prognosis of human hepatocellular carcinoma, Oncol. Rep., 11, 25
Altomare, 2005, Perturbations of the AKT signaling pathway in human cancer, Oncogene, 24, 7455, 10.1038/sj.onc.1209085
Parsons, 2005, Colorectal cancer: Mutations in a signalling pathway, Nature, 436, 792, 10.1038/436792a
Okano, 2000, Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation, J. Biol. Chem., 275, 30934, 10.1074/jbc.M004112200
Zhou, 2000, HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway, J. Biol. Chem., 275, 8027, 10.1074/jbc.275.11.8027
Datta, 1997, Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery, Cell, 91, 231, 10.1016/S0092-8674(00)80405-5
Cardone, 1998, Regulation of Cell Death Protease Caspase-9 by Phosphorylation, Science, 282, 1318, 10.1126/science.282.5392.1318
Tang, 1999, Negative regulation of the forkhead transcription factor FKHR by Akt, J. Biol. Chem., 274, 16741, 10.1074/jbc.274.24.16741
Brunet, 1999, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor, Cell, 96, 857, 10.1016/S0092-8674(00)80595-4
Ogawara, 2002, Akt enhances Mdm2-mediated ubiquitination and degradation of p53, J. Biol. Chem., 277, 21843, 10.1074/jbc.M109745200
Zhou, 2001, HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation, Nat. Cell Biol., 3, 973, 10.1038/ncb1101-973
Feng, 2004, Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation, J. Biol. Chem., 279, 35510, 10.1074/jbc.M404936200
Peterson, 2009, DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival, Cell, 137, 873, 10.1016/j.cell.2009.03.046
Shaw, 2006, Ras, PI(3)K and mTOR signalling controls tumour cell growth, Nature, 441, 424, 10.1038/nature04869
Huang, 2008, The TSC1-TSC2 complex: A molecular switchboard controlling cell growth, Biochem. J., 412, 179, 10.1042/BJ20080281
Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat. Cell Biol., 4, 648, 10.1038/ncb839
Manning, 2002, Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway, Mol. Cell, 10, 151, 10.1016/S1097-2765(02)00568-3
Ma, 2005, Phosphorylation and functional inactivation of TSC2 by Erk: Implications for tuberous sclerosis and cancer pathogenesis, Cell, 121, 179, 10.1016/j.cell.2005.02.031
Tee, 2002, Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling, Proc. Natl. Acad. Sci. USA, 99, 13571, 10.1073/pnas.202476899
Scott, 1998, Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway, Proc. Natl. Acad. Sci. USA, 95, 7772, 10.1073/pnas.95.13.7772
Dan, 2014, Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by IκB kinaseα (IKKα), J. Biol. Chem., 289, 25227, 10.1074/jbc.M114.554881
Keller, 2009, Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth, Mol. Cell. Biol., 29, 4308, 10.1128/MCB.01665-08
Abraham, 2004, mTOR as a positive regulator of tumor cell responses to hypoxia, Curr. Top. Microbiol. Immunol., 279, 299
Grewe, 1999, Regulation of cell growth and Cyclin D1 expression by the constitutively active FRAP-p70(s6K) pathway in human pancreatic cancer cells, Cancer Res., 59, 3581
Averous, 2008, Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1, Oncogene, 27, 1106, 10.1038/sj.onc.1210715
Cantley, 2009, Understanding the Warburg effect: The metabolic requirements of cell proliferation, Science, 324, 1029, 10.1126/science.1160809
Elstrom, 2004, Akt stimulates aerobic glycolysis in cancer cells, Cancer Res., 64, 3892, 10.1158/0008-5472.CAN-03-2904
Courtnay, 2015, Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K, Mol. Biol. Rep., 42, 841, 10.1007/s11033-015-3858-x
Lien, 2016, Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer, Recent Res. Cancer Res., 207, 39, 10.1007/978-3-319-42118-6_3
Nakamura, 2009, Roles of phospholipase C isozymes in organogenesis and embryonic development, Physiology, 24, 332, 10.1152/physiol.00031.2009
Ji, 1997, Essential role of the tyrosine kinase substrate phospholipase C-γ1 in mammalian growth and development, Proc. Natl. Acad. Sci. USA, 94, 2999, 10.1073/pnas.94.7.2999
Liao, 2002, Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice, J. Biol. Chem., 277, 9335, 10.1074/jbc.M109955200
Sala, 2008, Phospholipase Cgamma1 is required for metastasis development and progression, Cancer Res., 68, 10187, 10.1158/0008-5472.CAN-08-1181
Lattanzio, 2013, Role of phospholipase C in cell invasion and metastasis, Adv. Biol. Regul., 53, 309, 10.1016/j.jbior.2013.07.006
Rotin, 1992, SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: Identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C gamma, EMBO J., 11, 559, 10.1002/j.1460-2075.1992.tb05087.x
Anderson, 1990, Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors, Science, 250, 979, 10.1126/science.2173144
Chattopadhyay, 1999, The role of individual SH2 domains in mediating association of phospholipase C-γ1 with the activated EGF receptor, J. Biol. Chem., 274, 26091, 10.1074/jbc.274.37.26091
Falasca, 1998, Activation of phospholipase C gamma by PI 3-kinase-induced PH domain- mediated membrane targeting, EMBO J., 17, 414, 10.1093/emboj/17.2.414
Nishibe, 1990, Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation, Science, 250, 1253, 10.1126/science.1700866
Serrano, 2005, A New Tyrosine Phosphorylation Site in PLCγ1: The Role of Tyrosine 775 in Immune Receptor Signaling, J. Immunol., 174, 6233, 10.4049/jimmunol.174.10.6233
Gresset, 2010, Mechanism of phosphorylation-induced activation of phospholipase C-gamma isozymes, J. Biol. Chem., 285, 35836, 10.1074/jbc.M110.166512
Kang, 2012, Protein kinase C (PKC) isozyme-specific substrates and their design, Biotechnol. Adv., 30, 1662, 10.1016/j.biotechadv.2012.07.004
Cazaubon, 1994, Threonine-497 is a critical site for permissive activation of protein kinase C alpha, Biochem. J., 301, 443, 10.1042/bj3010443
Cazaubon, 1993, Identification of the phosphorylated region responsible for the permissive activation of protein kinase C, J. Biol. Chem., 268, 17559, 10.1016/S0021-9258(19)85369-3
Lund, 1990, Phosphorylation of the epidermal growth factor receptor at threonine 654 inhibits ligand-induced internalization and down-regulation, J. Biol. Chem., 265, 20517, 10.1016/S0021-9258(17)30533-1
Lee, 2009, The roles of phospholipase D in EGFR signaling, Biochim. Biophys. Acta, 1791, 862, 10.1016/j.bbalip.2009.04.007
Kim, 1999, Phosphorylation and activation of phospholipase D1 by protein kinase C in vivo: Determination of multiple phosphorylation sites, Biochemistry, 38, 10344, 10.1021/bi990579h
Song, 1994, Epidermal growth factor induces the production of biologically distinguishable diglyceride species from phosphatidylinositol and phosphatidylcholine via the independent activation of type C and type D phospholipases, Cell Growth Differ., 5, 79
Lu, 2000, Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts, Mol. Cell. Biol., 20, 462, 10.1128/MCB.20.2.462-467.2000
Joseph, 2001, Transformation of cells overexpressing a tyrosine kinase by phospholipase D1 and D2, Biochem. Biophys. Res. Commun., 289, 1019, 10.1006/bbrc.2001.6118
Rous, 1911, A Sarcoma of the Fowl Transmissible By an Agent Separable From the Tumor Cells, J. Exp. Med., 13, 397, 10.1084/jem.13.4.397
Xu, 1997, Three-dimensional structure of the tyrosine kinase c-Src, Nature, 385, 595, 10.1038/385595a0
Williams, 1997, The 2.35 A crystal structure of the inactivated form of chicken Src: A dynamic molecule with multiple regulatory interactions, J. Mol. Biol., 274, 757, 10.1006/jmbi.1997.1426
Cooper, 1986, Tyr527 is phosphorylated in pp60c-src: Implications for regulation, Science, 231, 1431, 10.1126/science.2420005
Okada, 1991, CSK: A protein-tyrosine kinase involved in regulation of src family kinases, J. Biol. Chem., 266, 24249, 10.1016/S0021-9258(18)54220-4
Okada, 2012, Regulation of the Src family kinases by Csk, Int. J. Biol. Sci., 8, 1385, 10.7150/ijbs.5141
Somani, 1997, Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase, J. Biol. Chem., 272, 21113, 10.1074/jbc.272.34.21113
Peng, 1995, Regulation of the Src tyrosine kinase and Syp tyrosine phosphatase by their cellular association, Oncogene, 11, 1955
Fang, 1994, Comparative study of three protein-tyrosine phosphatases. Chicken protein-tyrosine phosphatase lambda dephosphorylates c- Src tyrosine 527, J. Biol. Chem., 269, 20194, 10.1016/S0021-9258(17)32145-2
Charbonneau, 1989, Human placenta protein-tyrosine-phosphatase: Amino acid sequence and relationship to a family of receptor-like proteins, Proc. Natl. Acad. Sci. USA, 86, 5252, 10.1073/pnas.86.14.5252
Biscardi, 1999, c-Src-mediated Phosphorylation of the Epidermal Growth Factor Receptor on Tyr845 and Tyr1101 Is Associated with Modulation of Receptor Function, J. Biol. Chem., 274, 8335, 10.1074/jbc.274.12.8335
Hunter, 1980, Transforming gene product of Rous sarcoma virus phosphorylates tyrosine, Proc. Natl. Acad. Sci. USA, 77, 1311, 10.1073/pnas.77.3.1311
Collett, 1980, Avian sarcoma virus-transforming protein, pp60_src_ shows protein kinase activity specific for tyrosine, Nature, 285, 167, 10.1038/285167a0
Levinson, 1980, The purified product of the transforming gene of avian sarcoma virus phosphorylates tyrosine, J. Biol. Chem., 255, 11973, 10.1016/S0021-9258(19)70229-4
Sen, 2011, Regulation of Src Family Kinases in Human Cancers, J. Signal Transduct., 2011, 1, 10.1155/2011/865819
Thomas, 1997, Cellular functions regulated by Src family kinases, Annu. Rev. Cell Dev. Biol., 13, 513, 10.1146/annurev.cellbio.13.1.513
Bao, 2003, Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors, Proc. Natl. Acad. Sci. USA, 100, 2438, 10.1073/pnas.0437945100
Tice, 1999, Mechanism of biological synergy between cellular Src and epidermal growth factor receptor, Proc. Natl. Acad. Sci. USA, 96, 1415, 10.1073/pnas.96.4.1415
Goi, 2000, An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity, EMBO J., 19, 623, 10.1093/emboj/19.4.623
Maa, 1995, Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: Implications for the etiology of multiple human cancers, Proc. Natl. Acad. Sci. USA, 92, 6981, 10.1073/pnas.92.15.6981
Poole, 2011, Genetic variability in EGFR, Src and HER2 and risk of colorectal adenoma and cancer, Int. J. Mol. Epidemiol. Genet., 2, 300
Olayioye, 1999, ErbB receptor-induced activation of Stat transcription factors is mediated by Src tyrosine kinases, J. Biol. Chem., 274, 17209, 10.1074/jbc.274.24.17209
Sato, 1995, c-Src phosphorylates epidermal growth factor receptor on tyrosine 845, Biochem. Biophys. Res. Commun., 215, 1078, 10.1006/bbrc.1995.2574
Shan, 2012, Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization, Cell, 149, 860, 10.1016/j.cell.2012.02.063
Endoh, 2009, Immunohistochemical analysis of phosphorylated epidermal growth factor receptor might provide a surrogate marker of EGFR mutation, Lung Cancer, 63, 241, 10.1016/j.lungcan.2008.05.013
Chung, 2009, The role of cooperativity with Src in oncogenic transformation mediated by non-small cell lung cancer-associated EGF receptor mutants, Oncogene, 28, 1821, 10.1038/onc.2009.31
Mattila, 2005, Negative regulation of EGFR signalling through integrin-alpha1beta1-mediated activation of protein tyrosine phosphatase TCPTP, Nat. Cell Biol., 7, 78, 10.1038/ncb1209
Baumdick, M., Brüggemann, Y., Schmick, M., Xouri, G., Sabet, O., Davis, L., Chin, J.W., and Bastiaens, P.I.H. (2015). EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling. Elife, 4.
Koppikar, 2008, Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma, Clin. Cancer Res., 14, 4284, 10.1158/1078-0432.CCR-07-5226
Gargalionis, 2014, The molecular rationale of Src inhibition in colorectal carcinomas, Int. J. Cancer, 134, 2019, 10.1002/ijc.28299
Lin, 2001, Nuclear localization of EGF receptor and its potential new role as a transcription factor, Nat. Cell Biol., 3, 802, 10.1038/ncb0901-802
Cao, 1995, Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta, Endocrinology, 136, 3163, 10.1210/endo.136.7.7540549
Lo, 2006, Nuclear EGFR signalling network in cancers: Linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival, Br. J. Cancer, 94, 184, 10.1038/sj.bjc.6602941
Wang, 2010, Nuclear trafficking of the epidermal growth factor receptor family membrane proteins, Oncogene, 29, 3997, 10.1038/onc.2010.157
Lo, 2005, Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway, Cancer Cell, 7, 575, 10.1016/j.ccr.2005.05.007
Lee, 2015, Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response, Cell Res., 25, 225, 10.1038/cr.2015.8
Kamio, 1990, Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma, Hum. Pathol., 21, 277, 10.1016/0046-8177(90)90227-V
Lo, 2005, Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer, Cancer Res., 65, 338, 10.1158/0008-5472.338.65.1
Marti, 2001, Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues, Thyroid, 11, 137, 10.1089/105072501300042785
Psyrri, 2005, Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis, Clin. Cancer Res., 11, 5856, 10.1158/1078-0432.CCR-05-0420
Dittmann, 2010, Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr654, FEBS Lett., 584, 3878, 10.1016/j.febslet.2010.08.005
Liccardi, 2011, EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment, Cancer Res., 71, 1103, 10.1158/0008-5472.CAN-10-2384
Hsu, 2009, Nuclear EGFR is required for cisplatin resistance and DNA repair, Am. J. Transl. Res., 1, 249
Rodrigues, 2011, Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway, Biochem. Biophys. Res. Commun., 412, 341, 10.1016/j.bbrc.2011.07.100
Lo, 2006, Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1, J. Cell. Biochem., 98, 1570, 10.1002/jcb.20876
Wang, 2010, COPI-mediated retrograde trafficking from the Golgi to the ER regulates EGFR nuclear transport, Biochem. Biophys. Res. Commun., 399, 498, 10.1016/j.bbrc.2010.07.096
Jaganathan, S., Yue, P., Paladino, D.C., Bogdanovic, J., Huo, Q., and Turkson, J. (2011). A functional nuclear epidermal growth factor receptor, Src and Stat3 heteromeric complex in pancreatic cancer cells. PLoS ONE, 6.
Huo, 2010, RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus, Proc. Natl. Acad. Sci. USA, 107, 16125, 10.1073/pnas.1000743107
Bitler, 2010, MUC1 regulates nuclear localization and function of the EGFR, J. Cell Sci., 123, 1716, 10.1242/jcs.062661
Martinelli, 2009, Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy, Clin. Exp. Immunol., 158, 1, 10.1111/j.1365-2249.2009.03992.x
Ciardiello, 2008, EGFR Antagonists in Cancer Treatment, N. Engl. J. Med., 358, 1160, 10.1056/NEJMra0707704
Modjtahedi, 2009, Epidermal growth factor receptor inhibitors in cancer treatment: Advances, challenges and opportunities, Anticancer Drugs, 20, 851, 10.1097/CAD.0b013e3283330590
Shukuya, 2011, Efficacy of gefitinib for non-adenocarcinoma non-small-cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports, Cancer Sci., 102, 1032, 10.1111/j.1349-7006.2011.01887.x
Harandi, A., Zaidi, A.S., Stocker, A.M., and Laber, D.A. (2009). Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J. Oncol.
Lynch, 2004, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, N. Engl. J. Med., 350, 2129, 10.1056/NEJMoa040938
Bertotti, 2015, The genomic landscape of response to EGFR blockade in colorectal cancer, Nature, 526, 263, 10.1038/nature14969
Krasinskas, 2011, EGFR Signaling in Colorectal Carcinoma, Pathol. Res. Int., 2011, 932932, 10.4061/2011/932932
Chung, 2005, Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry, J. Clin. Oncol., 23, 1803, 10.1200/JCO.2005.08.037
Cunningham, 2004, Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer, N. Engl. J. Med., 351, 337, 10.1056/NEJMoa033025
Cayre, 2009, Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer, J. Clin. Oncol., 27, 5924, 10.1200/JCO.2008.21.6796
Cleary, 2015, A phase 1 study of ABT-806 in subjects with advanced solid tumors, Investig. New Drugs, 33, 671, 10.1007/s10637-015-0234-6
Benvenuti, 2007, Oncogenic Activation of the RAS / RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti—Epidermal Growth Factor Receptor Antibody Therapies, Cancer Res., 67, 2643, 10.1158/0008-5472.CAN-06-4158
Blanchard, 2007, Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy, Br. J. Cancer, 96, 1166, 10.1038/sj.bjc.6603685
Lievre, 2008, KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab, J. Clin. Oncol., 26, 374, 10.1200/JCO.2007.12.5906
Piessevaux, 2008, KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab, Ann. Oncol., 19, 508, 10.1093/annonc/mdm496
Cripps, 2010, Consensus recommendations for the use of anti-egfr therapies in metastatic colorectal cancer, Curr. Oncol., 17, 39, 10.3747/co.v17i6.670
Sorich, 2015, Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized controlled trials, Ann. Oncol., 26, 13, 10.1093/annonc/mdu378
Lovly, C.L., Horn, G., and Oxnard, W.P. (2015, October 15). EGFR c.2369C>T (T790M) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome. Available online: Https//www.mycancergenome.org/content/disease/lung-cancer/egfr/4/.
Zhang, 2012, Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer, Nat. Genet., 44, 852, 10.1038/ng.2330
Yauch, 2005, Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients, Clin. Cancer Res., 11, 8686, 10.1158/1078-0432.CCR-05-1492
Uramoto, 2010, Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma, Anticancer Res., 30, 2513
Suda, 2011, Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib, J. Thorac. Oncol., 7, 1152, 10.1097/JTO.0b013e318216ee52
Jakobsen, 2016, The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer, Transl. Lung Cancer Res., 5, 172, 10.21037/tlcr.2016.04.07
Peeters, 2010, Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer, J. Clin. Oncol., 28, 4706, 10.1200/JCO.2009.27.6055
Mitchell, 2009, Final STEPP results of prophylacatic versus reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)-related ST in patients (pts) with metastatic colorectal cancer (mCRC), J. Clin. Oncol., 27, CRA4027, 10.1200/jco.2009.27.18_suppl.cra4027
Park, 2016, Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial, Lancet Oncol., 17, 577, 10.1016/S1470-2045(16)30033-X
Huillard, 2014, Ocular adverse events of molecularly targeted agents approved in solid tumours: A systematic review, Eur. J. Cancer, 50, 638, 10.1016/j.ejca.2013.10.016
Johnson, 2009, Persistent corneal epithelial defect associated with erlotinib treatment, Cornea, 28, 706, 10.1097/ICO.0b013e31818fdbc6
Saceda, 2011, Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines, Exp. Cell Res., 317, 1476, 10.1016/j.yexcr.2011.03.015
Zhu, 2001, EGFR tyrosine kinase inhibitor AG1478 inhibits cell proliferation and arrests cell cycle in nasopharyngeal carcinoma cells, Cancer Lett., 169, 27, 10.1016/S0304-3835(01)00547-X
Giocanti, 2004, Additive interaction of gefitinib (‘Iressa’, ZD1839) and ionising radiation in human tumour cells in vitro, Br. J. Cancer, 91, 2026, 10.1038/sj.bjc.6602242
Busse, 2000, Reversible G1 arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity, J. Biol. Chem., 275, 6987, 10.1074/jbc.275.10.6987
Kiyota, 2002, Anti-epidermal growth factor receptor monoclonal antibody 225 upregulates p27(KIP1) and p15(INK4B) and induces G1 arrest in oral squamous carcinoma cell lines, Oncology, 63, 92, 10.1159/000065726
Gonzales, 2005, G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein, Exp. Cell Res., 303, 56
Huether, 2005, Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics, J. Hepatol., 43, 661, 10.1016/j.jhep.2005.02.040
Markaverich, 2010, Luteolin and gefitinib regulation of EGF signaling pathway and cell cycle pathway genes in PC-3 human prostate cancer cells, J. Steroid Biochem. Mol. Biol., 122, 219, 10.1016/j.jsbmb.2010.06.006
Ahn, 2014, Gefitinib induces cytoplasmic translocation of the CDK inhibitor p27 and its binding to a cleaved intermediate of caspase 8 in non-small cell lung cancer cells, Cell. Oncol., 37, 377, 10.1007/s13402-014-0198-0
Ma, 2014, AG1478 inhibits the migration and invasion of cisplatin-resistant human lung adenocarcinoma cells via the cell cycle regulation by matrix metalloproteinase-9, Oncol. Lett., 8, 921, 10.3892/ol.2014.2224
Haraldsdottir, 2013, Integrating anti-EGFR therapies in metastatic colorectal cancer, J. Gastrointest. Oncol., 4, 285
Li, 2013, Schmid-Bindert, G. Gefitinib-resistance is related to BIM expression in non-small cell lung cancer cell lines, Cancer Biother. Radiopharm., 28, 115
Luo, 2014, Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors, Am. J. Cancer Res., 4, 608
Misale, 2014, Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer, Sci. Transl. Med., 6, 224ra26, 10.1126/scitranslmed.3007947
Flaherty, 2012, Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma, N. Engl. J. Med., 367, 107, 10.1056/NEJMoa1203421
Flaherty, 2012, Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations, N. Engl. J. Med., 367, 1694, 10.1056/NEJMoa1210093
Huang, 2013, MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib, Mol. Oncol., 7, 112, 10.1016/j.molonc.2012.09.002
Turke, 2012, MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors, Cancer Res., 72, 3228, 10.1158/0008-5472.CAN-11-3747
Rexer, 2009, Inhibition of PI3K and MEK: It is all about combinations and biomarkers, Clin. Cancer Res., 15, 4518, 10.1158/1078-0432.CCR-09-0872
Posch, 2013, Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo, Proc. Natl. Acad. Sci. USA, 110, 4015, 10.1073/pnas.1216013110
Saini, 2013, Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer, Cancer Treat. Rev., 39, 935, 10.1016/j.ctrv.2013.03.009
Porta, 2014, Targeting PI3K/Akt/mTOR Signaling in Cancer, Front. Oncol., 4, 64, 10.3389/fonc.2014.00064
Harrington, 2004, The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins, J. Cell Biol., 166, 213, 10.1083/jcb.200403069
Chandarlapaty, 2011, AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity, Cancer Cell, 19, 58, 10.1016/j.ccr.2010.10.031
Chakrabarty, 2012, Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors, Proc. Natl. Acad. Sci. USA, 109, 2718, 10.1073/pnas.1018001108
Serra, 2011, PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer, Oncogene, 30, 2547, 10.1038/onc.2010.626
Chandarlapaty, 2011, mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling, Cancer Discov., 1, 248, 10.1158/2159-8290.CD-11-0085
Rojo, 2006, mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res., 66, 1500, 10.1158/0008-5472.CAN-05-2925
Amin, 2012, HER3 signalling is regulated through a multitude of redundant mechanisms in HER2-driven tumour cells, Biochem. J., 447, 417, 10.1042/BJ20120724
Tao, 2014, Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer, Sci. Signal., 7, ra29, 10.1126/scisignal.2005125
Garrett, 2013, Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110?? inhibitor potently blocks pi3k signaling and growth of HER2+ breast cancers, Cancer Res., 73, 6013, 10.1158/0008-5472.CAN-13-1191
Chen, 2010, Autophagy is a therapeutic target in anticancer drug resistance, Biochim. Biophys. Acta, 1806, 220
Zhou, 2017, CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma, Nat. Commun., 8, 13897, 10.1038/ncomms13897
Jones, 2001, Growth-factor-dependent mitogenesis requires two distinct phases of signalling, Nat. Cell Biol., 3, 165, 10.1038/35055073
Pennock, 2003, Stimulation of cell proliferation by endosomal epidermal growth factor receptor as revealed through two distinct phases of signaling, Mol. Cell. Biol., 23, 5803, 10.1128/MCB.23.16.5803-5815.2003
Kobayashi, 2006, Transcriptional profiling identifies Cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling, Cancer Res., 66, 11389, 10.1158/0008-5472.CAN-06-2318
Reissmann, 1999, Amplification and overexpression of the Cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer. Lung Cancer Study Group, J. Cancer Res. Clin. Oncol., 125, 61, 10.1007/s004320050243
McIntosh, 1995, Determination of the prognostic value of Cyclin D1 overexpression in breast cancer, Oncogene, 11, 885
Perry, 1998, Epidermal growth factor induces Cyclin D1 in a human prostate cancer cell line, Prostate, 35, 117, 10.1002/(SICI)1097-0045(19980501)35:2<117::AID-PROS5>3.0.CO;2-G
Narayanan, 2012, Epidermal growth factor-stimulated human cervical cancer cell growth is associated with EGFR and Cyclin D1 activation, independent of COX-2 expression levels, Int. J. Oncol., 40, 13
Chen, 2012, EGFR-mediated G1/S transition contributes to the multidrug resistance in breast cancer cells, Mol. Biol. Rep., 39, 5465, 10.1007/s11033-011-1347-4
Rubin, 2013, Deciphering the retinoblastoma protein phosphorylation code, Trends Biochem. Sci., 38, 12, 10.1016/j.tibs.2012.10.007
Hatakeyama, 1994, Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein, Genes Dev., 8, 1759, 10.1101/gad.8.15.1759
Yamamoto, 2006, Continuous ERK Activation Downregulates Antiproliferative Genes throughout G1 Phase to Allow Cell-Cycle Progression, Curr. Biol., 16, 1171, 10.1016/j.cub.2006.04.044
Hu, 1995, Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase, Science, 268, 100, 10.1126/science.7701328
Kim, 1999, Bone morphogenetic protein 2 inhibits platelet-derived growth factor-induced c-fos gene transcription and DNA synthesis in mesangial cells. Involvement of mitogen-activated protein kinase, J. Biol. Chem., 274, 10897, 10.1074/jbc.274.16.10897
Schmidt, 2002, Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D, Mol. Cell. Biol., 22, 7842, 10.1128/MCB.22.22.7842-7852.2002
Torii, 2006, ERK MAP kinase in G1 cell cycle progression and cancer, Cancer Sci., 97, 697, 10.1111/j.1349-7006.2006.00244.x
Diehl, 1998, Glycogen synthase kinase-3beta regulates Cyclin D1 proteolysis and subcellular localization, Genes Dev., 12, 3499, 10.1101/gad.12.22.3499
Welcker, 2003, Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation, Mol. Cell, 12, 381, 10.1016/S1097-2765(03)00287-9
Tullai, 2011, A GSK-3-mediated transcriptional network maintains repression of immediate early genes in quiescent cells, Cell Cycle, 10, 3072, 10.4161/cc.10.18.17321
Sutherland, 1993, Inactivation of glycogen synthase kinase-3fl by phosphorylation: New kinase connections in insulin and growth-factor signalling, Biochem. J., 296, 15, 10.1042/bj2960015
Stambolic, 1994, Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation, Biochem. J., 303, 701, 10.1042/bj3030701
Waskiewicz, 1997, Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2, EMBO J., 16, 1909, 10.1093/emboj/16.8.1909
Wang, 1998, The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways, J. Biol. Chem., 273, 9373, 10.1074/jbc.273.16.9373
Fry, 2004, Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts, Mol. Cancer Ther., 3, 1427, 10.1158/1535-7163.1427.3.11
Toogood, 2005, Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6, J. Med. Chem., 48, 2388, 10.1021/jm049354h
Asghar, 2015, The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug Discov., 14, 130, 10.1038/nrd4504
An, 1999, Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation, Am. J. Pathol., 154, 113, 10.1016/S0002-9440(10)65257-1
Mayer, 2015, Targeting Breast Cancer with CDK Inhibitors, Curr. Oncol. Rep., 17, 443, 10.1007/s11912-015-0443-3
Toyoshima, 1994, p27, A novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21, Cell, 78, 67, 10.1016/0092-8674(94)90573-8
Cheng, 1998, Assembly of cyclin D-dependent kinase and titration of p27KIP1 regulated by mitogen-activated protein kinase kinase (MEK1), Proc. Natl. Acad. Sci. USA, 95, 1091, 10.1073/pnas.95.3.1091
Katayose, 1997, Promoting apoptosis: A novel activity associated with the cyclin- dependent kinase inhibitor p27, Cancer Res., 57, 5441
Yang, 2013, p27KIP1 down-regulates egfr expression via inhibition of JNK/C-JUN transactivation: A novel function of p27KIP1 in tumor suppression deficient in metastatic bladder cancer cells, J. Urol., 189, e463
Fang, 2014, A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition, Biochem. J., 463, 383, 10.1042/BJ20140103
Rivard, 1999, MAP kinase cascade is required for p27 downregulation and S phase entry in fibroblasts and epithelial cells, Am. J. Physiol., 277, C652, 10.1152/ajpcell.1999.277.4.C652
Delmas, 2001, The p42/p44 mitogen-activated protein kinase activation triggers p27KIP1 degradation independently of CDK2/cyclin E in NIH 3T3 cells, J. Biol. Chem., 276, 34958, 10.1074/jbc.M101714200
Kortylewski, 2001, Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells, Biochem. J., 357, 297, 10.1042/bj3570297
Kawada, 1997, Induction of p27KIP1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway, Oncogene, 15, 629, 10.1038/sj.onc.1201228
Wu, 2003, Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter, Oncogene, 22, 351, 10.1038/sj.onc.1206145
Sahin, O., Fröhlich, H., Löbke, C., Korf, U., Burmester, S., Majety, M., Mattern, J., Schupp, I., Chaouiya, C., and Thieffry, D. (2009). Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance. BMC Syst. Biol., 3.
Liang, 2002, PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest, Nat. Med., 8, 1153, 10.1038/nm761
Katayama, 2005, Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition, Mol. Cell. Biol., 25, 5725, 10.1128/MCB.25.13.5725-5737.2005
Medema, 2000, AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1, Nature, 404, 782, 10.1038/35008115
Dijkers, 2000, Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1), Mol. Cell. Biol., 20, 9138, 10.1128/MCB.20.24.9138-9148.2000
Wang, 2008, p27KIP1 nuclear localization and cyclin-dependent kinase inhibitory activity are regulated by glycogen synthase kinase-3 in human colon cancer cells, Cell Death Differ., 15, 908, 10.1038/cdd.2008.2
Goh, 2010, Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor, J. Cell Biol., 189, 871, 10.1083/jcb.201001008
Wang, 2015, Dimerization drives EGF receptor endocytosis through two sets of compatible endocytic codes, J. Cell Sci., 128, 935
Levkowitz, 1998, c-Cb1/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor, Genes Dev., 12, 3663, 10.1101/gad.12.23.3663
Sousa, 2012, Suppression of EGFR endocytosis by dynamin depletion reveals that EGFR signaling occurs primarily at the plasma membrane, Proc. Natl. Acad. Sci. USA, 109, 4419, 10.1073/pnas.1200164109
Noh, 2008, Block copolymer micelles conjugated with anti-EGFR antibody for targeted delivery of anticancer drug, J. Polym. Sci. Part A Polym. Chem., 46, 7321, 10.1002/pola.23036
Maya, 2014, Actively targeted cetuximab conjugated gamma-poly(glutamic acid)-docetaxel nanomedicines for epidermal growth factor receptor over expressing colon cancer cells, J. Biomed. Nanotechnol., 10, 1416, 10.1166/jbn.2014.1841
Wee, 2015, EGF stimulates the activation of EGF receptors and the selective activation of major signaling pathways during mitosis, Cell Signal., 27, 638, 10.1016/j.cellsig.2014.11.030
Liu, 2011, Regulation of EGF-stimulated EGF receptor endocytosis during M phase, Traffic, 12, 201, 10.1111/j.1600-0854.2010.01141.x
Dangi, 2005, Cdc2-mediated inhibition of epidermal growth factor activation of the extracellular signal-regulated kinase pathway during mitosis, J. Biol. Chem., 280, 24524, 10.1074/jbc.M414079200