Signalling via integrins: Implications for cell survival and anticancer strategies

Barcellos-Hoff, 2005, Radiation and the microenvironment—Tumorigenesis and therapy, Nat. Rev., Cancer, 5, 867, 10.1038/nrc1735 Hanahan, 2000, The hallmarks of cancer, Cell, 100, 57, 10.1016/S0092-8674(00)81683-9 Lu, 2006, Inflammation, a key event in cancer development, Mol. Cancer Res., 4, 221, 10.1158/1541-7786.MCR-05-0261 Walenta, 2004, Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology, Curr. Med. Chem., 11, 2195, 10.2174/0929867043364711 Burridge, 1988, Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton, Annu. Rev. Cell. Biol., 4, 487, 10.1146/annurev.cb.04.110188.002415 Baselga, 2005, Critical update and emerging trends in epidermal growth factor receptor targeting in cancer, J. Clin. Oncol., 23, 2445, 10.1200/JCO.2005.11.890 Baker, 2003, The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer, Exp. Cell Res., 290, 177, 10.1016/S0014-4827(03)00342-2 Alghisi, 2006, Vascular integrins in tumor angiogenesis: mediators and therapeutic targets, Endothelium, 13, 113, 10.1080/10623320600698037 Moran, 2005, Radiotherapy: what can be achieved by technical improvements in dose delivery?, Lancet Oncol., 6, 51, 10.1016/S1470-2045(05)70026-7 Vaupel, 2004, Tumor microenvironmental physiology and its implications for radiation oncology, Semin. Radiat. Oncol., 14, 198, 10.1016/j.semradonc.2004.04.008 Wright, 2006, Untargeted effects of ionizing radiation: implications for radiation pathology, Mutat. Res., 597, 119, 10.1016/j.mrfmmm.2005.03.035 Hannigan, 1996, Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase, Nature, 379, 91, 10.1038/379091a0 Hynes, 2002, Integrins: bidirectional, allosteric signaling machines, Cell, 110, 673, 10.1016/S0092-8674(02)00971-6 Schaller, 2001, Biochemical signals and biological responses elicited by the focal adhesion kinase, Biochim. Biophys. Acta, 1540, 1, 10.1016/S0167-4889(01)00123-9 Wu, 2001, Integrin-linked kinase (ILK) and its interactors: a new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes, J. Cell Biol., 155, 505, 10.1083/jcb.200108077 Schwartz, 2002, Networks and crosstalk: integrin signalling spreads, Nat. Cell Biol., 4, E65, 10.1038/ncb0402-e65 Watt, 2002, Role of integrins in regulating epidermal adhesion, growth and differentiation, EMBO J., 21, 3919, 10.1093/emboj/cdf399 Brakebusch, 2003, The integrin–actin connection, an eternal love affair, EMBO J., 22, 2324, 10.1093/emboj/cdg245 Schwartz, 2001, Integrin signaling revisited, Trends Cell Biol, 11, 466, 10.1016/S0962-8924(01)02152-3 Schwartz, 2001, Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways, J. Cell Sci., 114, 2553, 10.1242/jcs.114.14.2553 Zahir, 2004, Death in the third dimension: apoptosis regulation and tissue architecture, Curr. Opin. Genet. Dev., 14, 71, 10.1016/j.gde.2003.12.005 Shimaoka, 2002, Conformational regulation of integrin structure and function, Annu. Rev. Biophys. Biomol. Struct., 31, 485, 10.1146/annurev.biophys.31.101101.140922 Rosales, 1995, Signal transduction by cell adhesion receptors, Biochim. Biophys. Acta, 1242, 77 Schaller, 1994, Focal adhesion kinase and associated proteins, Curr. Opin. Cell Biol., 6, 705, 10.1016/0955-0674(94)90097-3 Welsh, 2000, A growing role for Rho family GTPases as intermediaries in growth factor- and adhesion-dependent cell cycle progression, Biochim. Biophys. Acta, 1471, M21 Kinashi, 2005, Intracellular signalling controlling integrin activation in lymphocytes, Nat. Rev., Immunol., 5, 546, 10.1038/nri1646 Ginsberg, 2005, Integrin regulation, Curr. Opin. Cell Biol., 17, 509, 10.1016/j.ceb.2005.08.010 Legate, 2006, ILK, PINCH and parvin: the tIPP of integrin signalling, Nat. Rev., Mol. Cell Biol., 7, 20, 10.1038/nrm1789 Luo, 2004, A specific interface between integrin transmembrane helices and affinity for ligand, PLoS Biol., 2, e153, 10.1371/journal.pbio.0020153 Brown, 2002, Talin is essential for integrin function in Drosophila, Dev. Cell, 3, 569, 10.1016/S1534-5807(02)00290-3 Critchley, 2004, Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion, Biochem. Soc. Trans., 32, 831, 10.1042/BST0320831 Garcia-Alvarez, 2003, Structural determinants of integrin recognition by talin, Mol. Cell, 11, 49, 10.1016/S1097-2765(02)00823-7 Czuchra, 2006, Genetic analysis of {beta}1 integrin “activation motifs” in mice, J. Cell Biol., 174, 889, 10.1083/jcb.200604060 Tu, 1998, Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways, Mol. Biol. Cell, 9, 3367, 10.1091/mbc.9.12.3367 D'Ardenne, 1991, Co-ordinate expression of the alpha-6 integrin laminin receptor sub-unit and laminin in breast cancer, J. Pathol., 165, 213, 10.1002/path.1711650304 Felding-Habermann, 2003, Integrin adhesion receptors in tumor metastasis, Clin. Exp. Metastasis, 20, 203, 10.1023/A:1022983000355 Parise, 2000, New aspects of integrin signaling in cancer, Semin. Cancer Biol., 10, 407, 10.1006/scbi.2000.0337 Petersen, 1992, Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells [published erratum appears in Proc. Natl. Acad. Sci. U.S.A. 1993 Mar 15;90(6):2556], Proc. Natl. Acad. Sci. U. S. A., 89, 9064, 10.1073/pnas.89.19.9064 Wilhelmsen, 2006, Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis, Mol. Cell. Biol., 26, 2877, 10.1128/MCB.26.8.2877-2886.2006 Mercurio, 2001, Towards a mechanistic understanding of tumor invasion–lessons from the alpha6beta 4 integrin, Semin. Cancer Biol., 11, 129, 10.1006/scbi.2000.0364 Mizejewski, 1999, Role of integrins in cancer: survey of expression patterns, Proc. Soc. Exp. Biol. Med., 222, 124, 10.1046/j.1525-1373.1999.d01-122.x Bagutti, 1998, Comparison of integrin, cadherin, and catenin expression in squamous cell carcinomas of the oral cavity, J. Pathol., 186, 8, 10.1002/(SICI)1096-9896(199809)186:1<8::AID-PATH156>3.0.CO;2-H Van Waes, 1991, The A9 antigen associated with aggressive human squamous carcinoma is structurally and functionally similar to the newly defined integrin alpha 6 beta 4, Cancer Res., 51, 2395 Wang, 2004, Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis, J. Cell Biol., 164, 935, 10.1083/jcb.200309112 Evans, 2003, A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control, J. Cell Biol., 160, 589, 10.1083/jcb.200209016 Levy, 2000, beta1 integrins regulate keratinocyte adhesion and differentiation by distinct mechanisms, Mol. Biol. Cell, 11, 453, 10.1091/mbc.11.2.453 Evans, 2004, Sequence variation in the I-like domain of the beta1 integrin subunit in human oral squamous cell carcinomas, Cancer Lett., 213, 189, 10.1016/j.canlet.2004.05.013 Weaver, 1997, Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies, J. Cell Biol., 137, 231, 10.1083/jcb.137.1.231 Zutter, 1995, Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells, Proc. Natl. Acad. Sci. U. S. A., 92, 7411, 10.1073/pnas.92.16.7411 Carloni, 1998, Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells, Gastroenterology, 115, 433, 10.1016/S0016-5085(98)70210-0 Stroeken, 2000, Cytoplasmic domain mutants of beta1 integrin, expressed in beta 1-knockout lymphoma cells, have distinct effects on adhesion, invasion and metastasis, Oncogene, 19, 1232, 10.1038/sj.onc.1203423 Chen, 2006, In vivo beta1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines, Genes Dev., 20, 927, 10.1101/gad.1408306 Sakai, 2001, Role of the cytoplasmic tyrosines of beta 1A integrins in transformation by v-src, Proc. Natl. Acad. Sci. U. S. A., 98, 3808, 10.1073/pnas.240456398 Pozzi, 2000, Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization, Proc. Natl. Acad. Sci. U. S. A., 97, 2202, 10.1073/pnas.040378497 Hannigan, 1997, Mapping of the gene encoding the integrin-linked kinase, ILK, to human chromosome 11p15.5–p15.4, Genomics, 42, 177, 10.1006/geno.1997.4719 Melchior, 2002, Promoter characterization and genomic organization of the gene encoding integrin-linked kinase 1, Biochim. Biophys. Acta, 1575, 117, 10.1016/S0167-4781(02)00247-6 Tu, 1999, The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells, Mol. Cell. Biol., 19, 2425, 10.1128/MCB.19.3.2425 Leung-Hagesteijn, 2001, Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1, EMBO J., 20, 2160, 10.1093/emboj/20.9.2160 Rearden, 1994, A new LIM protein containing an autoepitope homologous to “senescent cell antigen”, Biochem. Biophys. Res. Commun., 201, 1124, 10.1006/bbrc.1994.1822 Li, 1999, Integrin-linked kinase is localized to cell–matrix focal adhesions but not cell–cell adhesion sites and the focal adhesion localization of integrin-linked kinase is regulated by the PINCH-binding ANK repeats, J. Cell Sci., 112, 4589, 10.1242/jcs.112.24.4589 Zhang, 2002, Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1–ILK interaction, cell spreading, and migration, J. Biol. Chem., 277, 38328, 10.1074/jbc.M205576200 Delcommenne, 1998, Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase, Proc. Natl. Acad. Sci. U. S. A., 95, 11211, 10.1073/pnas.95.19.11211 Nikolopoulos, 2000, Actopaxin, a new focal adhesion protein that binds paxillin LD motifs and actin and regulates cell adhesion, J. Cell Biol., 151, 1435, 10.1083/jcb.151.7.1435 Olski, 2001, Parvin, a 42 kDa focal adhesion protein, related to the alpha-actinin superfamily, J. Cell Sci., 114, 525, 10.1242/jcs.114.3.525 Tu, 2001, A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading, J. Cell Biol., 153, 585, 10.1083/jcb.153.3.585 Yamaji, 2001, A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell–substrate interaction, J. Cell Biol., 153, 1251, 10.1083/jcb.153.6.1251 Nikolopoulos, 2001, Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions, J. Biol. Chem., 276, 23499, 10.1074/jbc.M102163200 Nikolopoulos, 2002, Molecular dissection of actopaxin-integrin-linked kinase–Paxillin interactions and their role in subcellular localization, J. Biol. Chem., 277, 1568, 10.1074/jbc.M108612200 Fukuda, 2003, PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival, J. Biol. Chem., 278, 51324, 10.1074/jbc.M309122200 Li, 2005, PINCH1 regulates cell–matrix and cell–cell adhesions, cell polarity and cell survival during the peri-implantation stage, J. Cell Sci., 118, 2913, 10.1242/jcs.02422 Zhang, 2002, Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for localization of each component to cell–matrix adhesion sites, J. Cell Sci., 115, 4777, 10.1242/jcs.00166 Zhang, 2004, Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and beta-parvins, in regulation of cell morphology and survival, J. Biol. Chem., 279, 41695, 10.1074/jbc.M401563200 Guo, 2002, Regulation of fibronectin matrix deposition and cell proliferation by the PINCH-ILK-CH-ILKBP complex, FASEB J., 16, 1298, 10.1096/fj.02-0089fje Yang, 2005, Formation and phosphorylation of the PINCH-1-integrin linked kinase-alpha-parvin complex are important for regulation of renal glomerular podocyte adhesion, architecture, and survival, J. Am. Soc. Nephrol., 16, 1966, 10.1681/ASN.2004121112 Zhang, 2002, A critical role of the PINCH-integrin-linked kinase interaction in the regulation of cell shape change and migration, J. Biol. Chem., 277, 318, 10.1074/jbc.M108257200 Meisenhelder, 1992, The SH2/SH3 domain-containing protein Nck is recognized by certain anti-phospholipase C-gamma 1 monoclonal antibodies, and its phosphorylation on tyrosine is stimulated by platelet-derived growth factor and epidermal growth factor treatment, Mol. Cell. Biol., 12, 5843 Stein, 1998, Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase, J. Biol. Chem., 273, 1303, 10.1074/jbc.273.3.1303 Vaynberg, 2005, Structure of an ultraweak protein–protein complex and its crucial role in regulation of cell morphology and motility, Mol. Cell, 17, 513, 10.1016/j.molcel.2004.12.031 Velyvis, 2003, Structural and functional insights into PINCH LIM4 domain-mediated integrin signaling, Nat. Struct. Biol., 10, 558, 10.1038/nsb938 Lynch, 1999, Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism, Oncogene, 18, 8024, 10.1038/sj.onc.1203258 Troussard, 1999, Cell-extracellular matrix interactions stimulate the AP-1 transcription factor in an integrin-linked kinase- and glycogen synthase kinase 3-dependent manner, Mol. Cell. Biol., 19, 7420, 10.1128/MCB.19.11.7420 Persad, 2000, Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells, Proc. Natl. Acad. Sci. U. S. A., 97, 3207, 10.1073/pnas.97.7.3207 Persad, 2001, Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343, J. Biol. Chem., 276, 27462, 10.1074/jbc.M102940200 Feng, 2004, Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase, J. Biol. Chem., 279, 41189, 10.1074/jbc.M406731200 Hill, 2002, Identification of a plasma membrane Raft-associated PKB Ser473 kinase activity that is distinct from ILK and PDK1, Curr. Biol., 12, 1251, 10.1016/S0960-9822(02)00973-9 Grashoff, 2003, Integrin-linked kinase regulates chondrocyte shape and proliferation, EMBO Rep., 4, 432, 10.1038/sj.embor.embor801 Sakai, 2003, Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation, Genes Dev., 17, 926, 10.1101/gad.255603 Mackinnon, 2002, C. elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes, Curr. Biol., 12, 787, 10.1016/S0960-9822(02)00810-2 Zervas, 2002, Integrin adhesion: when is a kinase a kinase?, Curr. Biol., 12, R350, 10.1016/S0960-9822(02)00856-4 Zervas, 2001, Drosophila integrin-linked kinase is required at sites of integrin adhesion to link the cytoskeleton to the plasma membrane, J. Cell Biol., 152, 1007, 10.1083/jcb.152.5.1007 Wu, 2004, The PINCH–ILK–parvin complexes: assembly, functions and regulation, Biochim. Biophys. Acta, 1692, 55, 10.1016/j.bbamcr.2004.01.006 Diehl, 1998, Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization, Genes Dev., 12, 3499, 10.1101/gad.12.22.3499 Novak, 1998, Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways, Proc. Natl. Acad. Sci. U. S. A., 95, 4374, 10.1073/pnas.95.8.4374 Tan, 2001, Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC−/− human colon carcinoma cells, Oncogene, 20, 133, 10.1038/sj.onc.1204052 Tan, 2004, Regulation of tumor angiogenesis by integrin-linked kinase (ILK), Cancer Cell, 5, 79, 10.1016/S1535-6108(03)00281-2 Tan, 2002, Integrin-linked kinase regulates inducible nitric oxide synthase and cyclooxygenase-2 expression in an NF-kappa B-dependent manner, J. Biol. Chem., 277, 3109, 10.1074/jbc.M108673200 Makino, 2004, Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway, Oncogene, 23, 3883, 10.1038/sj.onc.1207485 Lee, 2006, Integrin-linked kinase, a hypoxia-responsive molecule, controls postnatal vasculogenesis by recruitment of endothelial progenitor cells to ischemic tissue, Circulation, 114, 150, 10.1161/CIRCULATIONAHA.105.595918 Troussard, 2000, The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9), Oncogene, 19, 5444, 10.1038/sj.onc.1203928 Attwell, 2003, Integration of cell attachment, cytoskeletal localization, and signaling by integrin-linked kinase (ILK), CH-ILKBP, and the tumor suppressor PTEN, Mol. Biol. Cell, 14, 4813, 10.1091/mbc.e03-05-0308 Di-Poi, 2002, Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway, Mol. Cell, 10, 721, 10.1016/S1097-2765(02)00646-9 Khyrul, 2004, The integrin-linked kinase regulates cell morphology and motility in a rho-associated kinase-dependent manner, J. Biol. Chem., 279, 54131, 10.1074/jbc.M410051200 Bishop, 2000, Rho GTPases and their effector proteins, Biochem. J., 348, 241, 10.1042/bj3480241 Etienne-Manneville, 2002, Rho GTPases in cell biology, Nature, 420, 629, 10.1038/nature01148 Hall, 2000, Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton, Philos. Trans. R. Soc. Lond., B Biol. Sci., 355, 965, 10.1098/rstb.2000.0632 Mitra, 2005, Focal adhesion kinase: in command and control of cell motility, Nat. Rev., Mol. Cell Biol., 6, 56, 10.1038/nrm1549 Riento, 2003, Rocks: multifunctional kinases in cell behaviour, Nat. Rev., Mol. Cell Biol., 4, 446, 10.1038/nrm1128 Boulter, 2006, Regulation of cell–matrix adhesion dynamics and Rac-1 by integrin linked kinase, FASEB J., 20, 1489, 10.1096/fj.05-4579fje Dai, 2003, Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival, Clin. Cancer Res., 9, 4409 Graff, 2001, Integrin-linked kinase expression increases with prostate tumor grade, Clin. Cancer Res., 7, 1987 Marotta, 2001, Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis, Oncogene, 20, 6250, 10.1038/sj.onc.1204791 Takanami, 2005, Increased expression of integrin-linked kinase is associated with shorter survival in non-small cell lung cancer, BMC Cancer, 5, 1, 10.1186/1471-2407-5-1 White, 2001, Mammary epithelial-specific expression of the integrin-linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice, Oncogene, 20, 7064, 10.1038/sj.onc.1204910 Dedhar, 2000, Cell–substrate interactions and signaling through ILK, Curr. Opin. Cell Biol., 12, 250, 10.1016/S0955-0674(99)00083-6 Guan, 1992, Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation, Nature, 358, 690, 10.1038/358690a0 Hanks, 1992, Focal adhesion protein–tyrosine kinase phosphorylated in response to cell attachment to fibronectin, Proc. Natl. Acad. Sci. U. S. A., 89, 8487, 10.1073/pnas.89.18.8487 Schaller, 1992, pp125FAK a structurally distinctive protein–tyrosine kinase associated with focal adhesions, Proc. Natl. Acad. Sci. U. S. A., 89, 5192, 10.1073/pnas.89.11.5192 Chen, 2001, Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain, Nat. Cell Biol., 3, 439, 10.1038/35074500 Poullet, 2001, Ezrin interacts with focal adhesion kinase and induces its activation independently of cell–matrix adhesion, J. Biol. Chem., 276, 37686, 10.1074/jbc.M106175200 Sieg, 2000, FAK integrates growth-factor and integrin signals to promote cell migration, Nat. Cell Biol., 2, 249, 10.1038/35010517 Kadare, 2003, PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation, J. Biol. Chem., 278, 47434, 10.1074/jbc.M308562200 Chodniewicz, 2004, Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold, Biochim. Biophys. Acta, 1692, 63, 10.1016/j.bbamcr.2004.03.006 Hanks, 2003, Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility, Front. Biosci., 8, d982, 10.2741/1114 Hayashi, 2002, The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin, Nat. Struct. Biol., 9, 101, 10.1038/nsb755 Schlaepfer, 2004, Control of motile and invasive cell phenotypes by focal adhesion kinase, Biochim. Biophys. Acta, 1692, 77, 10.1016/j.bbamcr.2004.04.008 Zhai, 2003, Direct interaction of focal adhesion kinase with p190RhoGEF, J. Biol. Chem., 278, 24865, 10.1074/jbc.M302381200 Calalb, 1995, Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases, Mol. Cell. Biol., 15, 954, 10.1128/MCB.15.2.954 Sakai, 1994, A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner, EMBO J., 13, 3748, 10.1002/j.1460-2075.1994.tb06684.x Tachibana, 1995, Direct association of pp125FAK with paxillin, the focal adhesion-targeting mechanism of pp125FAK, J. Exp. Med., 182, 1089, 10.1084/jem.182.4.1089 Lim, 2004, Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts, J. Biol. Chem., 279, 29060, 10.1074/jbc.M401183200 Schaller, 2001, Paxillin: a focal adhesion-associated adaptor protein, Oncogene, 20, 6459, 10.1038/sj.onc.1204786 Turner, 2000, Paxillin and focal adhesion signalling, Nat. Cell Biol., 2, E231, 10.1038/35046659 Schlaepfer, 1997, Fibronectin-stimulated signaling from a focal adhesion kinase-c–Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins, Mol. Cell. Biol., 17, 1702, 10.1128/MCB.17.3.1702 Chiarugi, 2003, Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion, J. Cell Biol., 161, 933, 10.1083/jcb.200211118 Zeng, 2003, PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration, J. Cell Biol., 160, 137, 10.1083/jcb.200206049 Ilic, 1995, Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice, Nature, 377, 539, 10.1038/377539a0 Palazzo, 2004, Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling, Science, 303, 836, 10.1126/science.1091325 Webb, 2004, FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly, Nat. Cell Biol., 6, 154, 10.1038/ncb1094 Ren, 2000, Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover, J. Cell Sci., 113, 3673, 10.1242/jcs.113.20.3673 Chen, 2002, Roles of Rho-associated kinase and myosin light chain kinase in morphological and migratory defects of focal adhesion kinase-null cells, J. Biol. Chem., 277, 33857, 10.1074/jbc.M204429200 Chang, 1995, c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation, J. Cell Biol., 130, 355, 10.1083/jcb.130.2.355 Bhattacharjee, 2001, Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses, Proc. Natl. Acad. Sci. U. S. A., 98, 13790, 10.1073/pnas.191502998 Yeoh, 2002, Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling, Cancer Cell, 1, 133, 10.1016/S1535-6108(02)00032-6 Agochiya, 1999, Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells, Oncogene, 18, 5646, 10.1038/sj.onc.1202957 Hauck, 2002, v-Src SH3-enhanced interaction with focal adhesion kinase at beta 1 integrin-containing invadopodia promotes cell invasion, J. Biol. Chem., 277, 12487, 10.1074/jbc.C100760200 Hsia, 2003, Differential regulation of cell motility and invasion by FAK, J. Cell Biol., 160, 753, 10.1083/jcb.200212114 Lehmann, 1990, Nck, a melanoma cDNA encoding a cytoplasmic protein consisting of the src homology units SH2 and SH3, Nucleic Acids Res., 18, 1048, 10.1093/nar/18.4.1048 Chen, 1998, Identification of Nck family genes, chromosomal localization, expression, and signaling specificity, J. Biol. Chem., 273, 25171, 10.1074/jbc.273.39.25171 Waksman, 1993, Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms, Cell, 72, 779, 10.1016/0092-8674(93)90405-F Bladt, 2003, The murine Nck SH2/SH3 adaptors are important for the development of mesoderm-derived embryonic structures and for regulating the cellular actin network, Mol. Cell. Biol., 23, 4586, 10.1128/MCB.23.13.4586-4597.2003 Jones, 2006, Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes, Nature, 440, 818, 10.1038/nature04662 Li, 2001, Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton, Oncogene, 20, 6403, 10.1038/sj.onc.1204782 Goicoechea, 2002, Nck-2 interacts with focal adhesion kinase and modulates cell motility, Int. J. Biochem. Cell. Biol., 34, 791, 10.1016/S1357-2725(02)00002-X Tu, 2001, Src homology 3 domain-dependent interaction of Nck-2 with insulin receptor substrate-1, Biochem. J., 354, 315, 10.1042/bj3540315 Chen, 2000, Nckbeta adapter regulates actin polymerization in NIH 3T3 fibroblasts in response to platelet-derived growth factor bb, Mol. Cell. Biol., 20, 7867, 10.1128/MCB.20.21.7867-7880.2000 Li, 1992, The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors, Mol. Cell. Biol., 12, 5824 Yamaguchi, 2005, Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin, J. Cell Biol., 168, 441, 10.1083/jcb.200407076 Stoletov, 2001, NCK and PAK participate in the signaling pathway by which vascular endothelial growth factor stimulates the assembly of focal adhesions, J. Biol. Chem., 276, 22748, 10.1074/jbc.M009720200 Braverman, 1999, Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck, J. Biol. Chem., 274, 5542, 10.1074/jbc.274.9.5542 Braun, 2003, PINCH2 is a new five LIM domain protein, homologous to PINCHand localized to focal adhesions, Exp. Cell Res., 284, 239, 10.1016/S0014-4827(02)00039-3 Velyvis, 2001, Solution structure of the focal adhesion adaptor PINCH LIM1 domain and characterization of its interaction with the integrin-linked kinase ankyrin repeat domain, J. Biol. Chem., 276, 4932, 10.1074/jbc.M007632200 Wu, 1999, Integrin-linked kinase and PINCH: partners in regulation of cell–extracellular matrix interaction and signal transduction, J. Cell Sci., 112, 4485, 10.1242/jcs.112.24.4485 Xu, 2005, Molecular dissection of PINCH-1 reveals a mechanism of coupling and uncoupling of cell shape modulation and survival, J. Biol. Chem., 280, 27631, 10.1074/jbc.M504189200 Masuelli, 1996, Increased expression of the Ras suppressor Rsu-1 enhances Erk-2 activation and inhibits Jun kinase activation, Mol. Cell. Biol., 16, 5466, 10.1128/MCB.16.10.5466 Dougherty, 2005, The Ras suppressor Rsu-1 binds to the LIM 5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions, Exp. Cell Res., 306, 168, 10.1016/j.yexcr.2005.01.025 Bock-Marquette, 2004, Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair, Nature, 432, 466, 10.1038/nature03000 Liang, 2005, PINCH1 plays an essential role in early murine embryonic development but is dispensable in ventricular cardiomyocytes, Mol. Cell. Biol., 25, 3056, 10.1128/MCB.25.8.3056-3062.2005 Stanchi, 2005, Consequences of loss of PINCH2 expression in mice, J. Cell Sci., 118, 5899, 10.1242/jcs.02686 Wang-Rodriguez, 2002, The signaling adapter protein PINCH is up-regulated in the stroma of common cancers, notably at invasive edges, Cancer, 95, 1387, 10.1002/cncr.10878 Gao, 2004, Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer, Neoplasia, 6, 796, 10.1593/neo.04304 Onoda, 1992, Radiation-induced increase in expression of the alpha IIb beta 3 integrin in melanoma cells: effects on metastatic potential, Radiat. Res., 130, 281, 10.2307/3578372 Cordes, 2002, Ionizing radiation induces up-regulation of functional beta1-integrin in human lung tumour cell lines in vitro, Int. J. Radiat. Biol., 78, 347, 10.1080/09553000110117340 Cordes, 2003, Cell adhesion-mediated radioresistance (CAM-RR). Extracellular matrix-dependent improvement of cell survival in human tumor and normal cells in vitro, Strahlenther. Onkol., 179, 337, 10.1007/s00066-003-1074-4 Damiano, 1999, Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines, Blood, 93, 1658, 10.1182/blood.V93.5.1658 Meineke, 2002, Ionizing radiation modulates cell surface integrin expression and adhesion of COLO-320 cells to collagen and fibronectin in vitro, Strahlenther. Onkol., 178, 709, 10.1007/s00066-002-0993-9 Addison, 2006, Modulation of response to tumor therapies by the extracellular matrix, Future Oncol., 2, 417, 10.2217/14796694.2.3.417 Cordes, 2006, beta1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury, Oncogene, 25, 1378, 10.1038/sj.onc.1209164 Cordes, 2003, Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3beta (GSK-3beta) in vitro, Br. J. Cancer, 88, 1470, 10.1038/sj.bjc.6600912 Damiano, 2001, Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation, Leukemia, 15, 1232, 10.1038/sj.leu.2402179 Eke, 2006, Antiproliferative effects of EGFR tyrosine kinase inhibition and radiation-induced genotoxic injury are attenuated by adhesion to fibronectin, Radiother. Oncol., 80, 178, 10.1016/j.radonc.2006.07.028 Hazlehurst, 2000, Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR), Oncogene, 19, 4319, 10.1038/sj.onc.1203782 Hess, 2006, Integrin-linked kinase interacts with caspases in an adhesion-dependent manner for promoting radiation-induced apoptosis in human HL60 acute promyelocytic leukemia cells, Oncogene Rose, 1999, The role of laminin-1 in the modulation of radiation damage in endothelial cells and differentiation, Radiat. Res., 152, 14, 10.2307/3580045 Sethi, 1999, Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo, Nat. Med., 5, 662, 10.1038/9511 Kremer, 2005, Integrin-dependent amplification of the G2 arrest induced by ionizing radiation, Prostate, 66, 88, 10.1002/pros.20316 Cordes, 2004, Arrest of human lung fibroblasts in G2 phase after irradiation is regulated by converging phosphatidylinositol-3 kinase and beta1-integrin signaling in vitro, Int. J. Radiat. Oncol. Biol. Phys., 58, 453, 10.1016/j.ijrobp.2003.09.069 Dimitrijevic-Bussod, 1999, Extracellular matrix and radiation G1 cell cycle arrest in human fibroblasts, Cancer Res., 59, 4843 de la Fuente, 2002, Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine, J. Leukocyte Biol., 71, 495, 10.1189/jlb.71.3.495 Gendron, 2003, Integrin alpha2beta1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway, J. Biol. Chem., 278, 48633, 10.1074/jbc.M305169200 Aoudjit, 2001, Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells, Oncogene, 20, 4995, 10.1038/sj.onc.1204554 Zhang, 2002, Beta 1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway, Cancer, 95, 896, 10.1002/cncr.10751 Hoyt, 1997, Integrin activation protects pulmonary endothelial cells from the genotoxic effects of bleomycin, Am. J. Physiol., 273, L612 Munger, 2004, The integrin alpha-v-beta-6-Knockout mouse is protected from Radiation-Induced Lung Fibrosis: implications for the clinic, Int. J. Radiat. Oncol. Biol. Phys., 60, S363, 10.1016/j.ijrobp.2004.07.147 Mueller-Klieser, 1997, Three-dimensional cell cultures: from molecular mechanisms to clinical applications, Am. J. Physiol., 273, C1109, 10.1152/ajpcell.1997.273.4.C1109 Durand, 1975, Cure, regression and cell survival: a comparison of common radiobiological endpoints using an in vitro tumour model, Br. J. Radiol., 48, 556, 10.1259/0007-1285-48-571-556 Durand, 1986, Chemosensitivity testing in V79 spheroids: drug delivery and cellular microenvironment, J. Natl. Cancer Inst., 77, 247 Durand, 2001, Resistance of tumor cells to chemo- and radiotherapy modulated by the three-dimensional architecture of solid tumors and spheroids, Methods Cell Biol., 64, 211, 10.1016/S0091-679X(01)64015-9 Dertinger, 1981, Increased radioresistance of cells in cultured multicell spheroids: I. Dependence on cellular interaction, Radiat. Environ. Biophys., 19, 101, 10.1007/BF01324226 Cordes, 2004, Overexpression of hyperactive integrin-linked kinase leads to increased cellular radiosensitivity, Cancer Res., 64, 5683, 10.1158/0008-5472.CAN-04-1056 Duxbury, 2005, RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance, Clin. Cancer Res., 11, 3433, 10.1158/1078-0432.CCR-04-1510 Younes, 2005, Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer, Mol. Cancer Ther., 4, 1146, 10.1158/1535-7163.MCT-05-0078 Edwards, 2006, Combined inhibition of the phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways results in synergistic effects in glioblastoma cells, Mol. Cancer Ther., 5, 645, 10.1158/1535-7163.MCT-05-0099 Blumenthal, 2005, An overview of chemosensitivity testing, Methods Mol. Med., 110, 3 Ross, 1999, Induction of cell death by radiotherapy, Endocr. Relat. Cancer, 6, 41, 10.1677/erc.0.0060041 Kasahara, 2002, Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation, Antioxid. Redox Signal., 4, 491, 10.1089/15230860260196290 Tamagiku, 2004, Down-regulation of procaspase-8 expression by focal adhesion kinase protects HL-60 cells from TRAIL-induced apoptosis, Biochem. Biophys. Res. Commun., 323, 445, 10.1016/j.bbrc.2004.08.115 Duxbury, 2004, Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells, Surgery, 135, 555, 10.1016/j.surg.2003.10.017 Smith, 2005, Effect of focal adhesion kinase (FAK) downregulation with FAK antisense oligonucleotides and 5-fluorouracil on the viability of melanoma cell lines, Melanoma Res., 15, 357, 10.1097/00008390-200510000-00003 Beinke, 2003, Ionizing radiation modulates expression and tyrosine phosphorylation of the focal adhesion-associated proteins focal adhesion kinase (FAK) and its substrates p130cas and paxillin in A549 human lung carcinoma cells in vitro, Int. J. Radiat. Biol., 79, 721, 10.1080/09553000310001610231 Landowski, 2003, Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells, Oncogene, 22, 2417, 10.1038/sj.onc.1206315 Hazlehurst, 2001, Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies, Cancer Metastasis. Rev., 20, 43, 10.1023/A:1013156407224 Weaver, 2002, beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium, Cancer Cell, 2, 205, 10.1016/S1535-6108(02)00125-3 Leclerc, 2002, Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions, Crit. Care Med., 30, S332, 10.1097/00003246-200205001-00025 Mousa, 2002, Anti-integrin as novel drug-discovery targets: potential therapeutic and diagnostic implications, Curr. Opin. Chem. Biol., 6, 534, 10.1016/S1367-5931(02)00350-2 Tucker, 2002, Inhibitors of integrins, Curr. Opin. Pharmacol., 2, 394, 10.1016/S1471-4892(02)00175-3 Baumann, 2004, Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results, Radiother. Oncol., 72, 257, 10.1016/j.radonc.2004.07.007 Cardones, 2006, VEGF inhibitors in cancer therapy, Curr. Pharm. Des., 12, 387, 10.2174/138161206775201910 Chinnaiyan, 2006, Clinical advancement of EGFR inhibitors in cancer therapy, Methods Mol. Biol., 327, 189 Wick, 2006, Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma, Curr. Pharm. Des., 12, 341, 10.2174/138161206775201901 Milenic, 2004, Antibody-targeted radiation cancer therapy, Nat. Rev., Drug Discov., 3, 488, 10.1038/nrd1413 Ruegg, 2004, Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis, Biochim. Biophys. Acta, 1654, 51 Patel, 2001, Pilot study of vitaxin–an angiogenesis inhibitor-in patients with advanced leiomyosarcomas, Cancer, 92, 1347, 10.1002/1097-0142(20010901)92:5<1347::AID-CNCR1456>3.0.CO;2-0 Gutheil, 2000, Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3, Clin. Cancer Res., 6, 3056 Posey, 2001, A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer, Cancer Biother. Radiopharm., 16, 125, 10.1089/108497801300189218 Raguse, 2004, Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour, Oral Oncol., 40, 228, 10.1016/j.oraloncology.2003.08.003 Burke, 2002, Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts, Cancer Res., 62, 4263 Smith, 2003, Cilengitide Merck, Curr. Opin. Investig. Drugs, 4, 741 Eskens, 2003, Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours, Eur. J. Cancer, 39, 917, 10.1016/S0959-8049(03)00057-1 Maglott, 2006, The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells, Cancer Res., 66, 6002, 10.1158/0008-5472.CAN-05-4105 Sabherwal, 2006, Integrin alpha2beta1 mediates the anti-angiogenic and anti-tumor activities of angiocidin, a novel tumor-associated protein, Exp. Cell Res., 312, 2443, 10.1016/j.yexcr.2006.04.009 Park, 2006, Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo, Cancer Res., 66, 1526, 10.1158/0008-5472.CAN-05-3071