Does Ras Activate Raf and PI3K Allosterically?

Tsai, 2014, A unified view of “how allostery works”, PLoS Comput Biol, 10, e1003394, 10.1371/journal.pcbi.1003394

Liu, 2016, Allostery: an overview of its history, concepts, methods, and applications, PLoS Comput Biol, 12, e1004966, 10.1371/journal.pcbi.1004966

Nussinov, 2016, Introduction to protein ensembles and allostery, Chem Rev, 116, 6263, 10.1021/acs.chemrev.6b00283

Boehr, 2009, The role of dynamic conformational ensembles in biomolecular recognition, Nat Chem Biol, 5, 789, 10.1038/nchembio.232

Buckles, 2017, Single-molecule study reveals how receptor and ras synergistically activate PI3Kalpha and PIP3 signaling, Biophys J, 113, 2396, 10.1016/j.bpj.2017.09.018

Zhang, 2019, The structural basis for Ras activation of PI3Kalpha lipid kinase, Phys Chem Chem Phys, 21, 12021, 10.1039/C9CP00101H

Nolte, 1996, Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes, Nat Struct Biol, 3, 364, 10.1038/nsb0496-364

Gabelli, 2014, Activation of PI3Kalpha by physiological effectors and by oncogenic mutations: structural and dynamic effects, Biophys Rev, 6, 89, 10.1007/s12551-013-0131-1

Nussinov, 2018, Autoinhibition in Ras effectors Raf, PI3Kalpha, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention, Biophys Rev, 10, 1263, 10.1007/s12551-018-0461-0

Terrell, 2019, Ras-mediated activation of the raf family kinases, Cold Spring Harb Perspect Med, 9, a033746, 10.1101/cshperspect.a033746

Lavoie, 2015, Regulation of RAF protein kinases in ERK signalling, Nat Rev Mol Cell Biol, 16, 281, 10.1038/nrm3979

Chuang, 1994, Critical binding and regulatory interactions between Ras and Raf occur through a small, stable N-terminal domain of Raf and specific Ras effector residues, Mol Cell Biol, 14, 5318, 10.1128/MCB.14.8.5318

Herrmann, 1995, Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase, J Biol Chem, 270, 2901, 10.1074/jbc.270.7.2901

Pauptit, 2001, NMR trial models: experiences with the colicin immunity protein Im7 and the p85alpha C-terminal SH2-peptide complex, Acta Crystallogr D Biol Crystallogr, 57, 1397, 10.1107/S0907444901012434

Zhang, 2019, The mechanism of PI3Kalpha activation at the atomic level, Chem Sci, 10, 3671, 10.1039/C8SC04498H

Karasarides, 2001, A direct interaction between oncogenic Ha-Ras and phosphatidylinositol 3-kinase is not required for Ha-Ras-dependent transformation of epithelial cells, J Biol Chem, 276, 39755, 10.1074/jbc.M102401200

Liao, 2016, RASSF5: an MST activator and tumor suppressor in vivo but opposite in vitro, Curr Opin Struct Biol, 41, 217, 10.1016/j.sbi.2016.09.001

Liao, 2017, The dynamic mechanism of RASSF5 and MST kinase activation by Ras, Phys Chem Chem Phys, 19, 6470, 10.1039/C6CP08596B

Stephens, 2005, Phosphoinositide 3-kinases as drug targets in cancer, Curr Opin Pharmacol, 5, 357, 10.1016/j.coph.2005.03.002

Jambrina, 2014, Molecular mechanisms of asymmetric RAF dimer activation, Biochem Soc Trans, 42, 784, 10.1042/BST20140025

Joseph, 2010, The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner, Proc Natl Acad Sci USA, 107, 14903, 10.1073/pnas.1008990107

Poulikakos, 2010, RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF, Nature, 464, 427, 10.1038/nature08902

Vadas, 2011, Structural basis for activation and inhibition of class I phosphoinositide 3-kinases, Sci Signal, 4, re2, 10.1126/scisignal.2002165

Ruan, 2018, Altered conformational landscape and dimerization dependency underpins the activation of EGFR by alphaC-beta4 loop insertion mutations, Proc Natl Acad Sci USA, 115, E8162, 10.1073/pnas.1803152115

Hubbard, 2014, Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: emerging therapeutic opportunities, Front Physiol, 5, 478, 10.3389/fphys.2014.00478

Tsai, 2018, Allosteric activation of RAF in the MAPK signaling pathway, Curr Opin Struct Biol, 53, 100, 10.1016/j.sbi.2018.07.007

Nussinov, 2015, Allostery without a conformational change? Revisiting the paradigm, Curr Opin Struct Biol, 30, 17, 10.1016/j.sbi.2014.11.005

Guo, 2016, Protein allostery and conformational dynamics, Chem Rev, 116, 6503, 10.1021/acs.chemrev.5b00590

Smith, 2019, Conformational dynamics and allosteric regulation landscapes of germline PTEN mutations associated with autism compared to those associated with cancer, Am J Hum Genet, 104, 861, 10.1016/j.ajhg.2019.03.009

Nussinov, 2013, The underappreciated role of allostery in the cellular network, Annu Rev Biophys, 42, 169, 10.1146/annurev-biophys-083012-130257

Nussinov, 2013, Allostery in disease and in drug discovery, Cell, 153, 293, 10.1016/j.cell.2013.03.034

Del Sol, 2009, The origin of allosteric functional modulation: multiple pre-existing pathways, Structure, 17, 1042, 10.1016/j.str.2009.06.008

Gardino, 2009, Transient non-native hydrogen bonds promote activation of a signaling protein, Cell, 139, 1109, 10.1016/j.cell.2009.11.022

Astl, 2019, Atomistic Modeling of the ABL kinase regulation by allosteric modulators using structural perturbation analysis and community-based network reconstruction of allosteric communications, J Chem Theory Comput, 15, 3362, 10.1021/acs.jctc.9b00119

Pfleger, 2017, Ensemble- and rigidity theory-based perturbation approach to analyze dynamic allostery, J Chem Theory Comput, 13, 6343, 10.1021/acs.jctc.7b00529

Ettayapuram Ramaprasad, 2017, Decomposing dynamical couplings in mutated scFv antibody fragments into stabilizing and destabilizing effects, J Am Chem Soc, 139, 17508, 10.1021/jacs.7b09268

Saleh, 2017, Investigating allosteric effects on the functional dynamics of beta2-adrenergic ternary complexes with enhanced-sampling simulations, Chem Sci, 8, 4019, 10.1039/C6SC04647A

Onel, 2017, Cullin neddylation may allosterically tune polyubiquitin chain length and topology, Biochem J, 474, 781, 10.1042/BCJ20160748

Zhan, 2016, Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization, Protein Eng Des Sel, 29, 347, 10.1093/protein/gzw033

Nussinov, 2015, The design of covalent allosteric drugs, Annu Rev Pharmacol Toxicol, 55, 249, 10.1146/annurev-pharmtox-010814-124401

Lu, 2017, Designed covalent allosteric modulators: an emerging paradigm in drug discovery, Drug Discov Today, 22, 447, 10.1016/j.drudis.2016.11.013

Bradshaw, 2015, Prolonged and tunable residence time using reversible covalent kinase inhibitors, Nat Chem Biol, 11, 525, 10.1038/nchembio.1817

Tsai, 2019, Emerging allosteric mechanism of EGFR activation in physiological and pathological contexts, Biophys J, 117, 5, 10.1016/j.bpj.2019.05.021

Zhao, 2019, Antigen binding allosterically promotes Fc receptor recognition, MAbs, 11, 58, 10.1080/19420862.2018.1522178

Liao, 2018, Allosteric KRas4B can modulate SOS1 Fast and slow ras activation cycles, Biophys J, 115, 629, 10.1016/j.bpj.2018.07.016

Verkhivker, 2019, Biophysical simulations and structure-based modeling of residue interaction networks in the tumor suppressor proteins reveal functional role of cancer mutation hotspots in molecular communication, Biochim Biophys Acta Gen Subj, 1863, 210, 10.1016/j.bbagen.2018.10.009

Daily, 2008, Contact rearrangements form coupled networks from local motions in allosteric proteins, Proteins, 71, 455, 10.1002/prot.21800

Papaleo, 2016, The role of protein loops and linkers in conformational dynamics and allostery, Chem Rev, 116, 6391, 10.1021/acs.chemrev.5b00623

Ma, 2011, Dynamic allostery: linkers are not merely flexible, Structure, 19, 907, 10.1016/j.str.2011.06.002

Thorpe, 2017, PI3K-p110alpha mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85alpha, Proc Natl Acad Sci USA, 114, 7095, 10.1073/pnas.1704706114

Castellano, 2011, RAS Interaction with PI3K: more than just another effector pathway, Genes Cancer, 2, 261, 10.1177/1947601911408079

Murillo, 2014, RAS interaction with PI3K p110alpha is required for tumor-induced angiogenesis, J Clin Invest, 124, 3601, 10.1172/JCI74134

Burke, 2012, Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110alpha (PIK3CA), Proc Natl Acad Sci USA, 109, 15259, 10.1073/pnas.1205508109

Tsutsumi, 2009, Visualization of Ras-PI3K interaction in the endosome using BiFC, Cell Signal, 21, 1672, 10.1016/j.cellsig.2009.07.004

Wang, 2008, Protein interaction data set highlighted with human Ras-MAPK/PI3K signaling pathways, J Proteome Res, 7, 3879, 10.1021/pr8001645

Jang, 2017, Flexible-body motions of calmodulin and the farnesylated hypervariable region yield a high-affinity interaction enabling K-Ras4B membrane extraction, J Biol Chem, 292, 12544, 10.1074/jbc.M117.785063

Nussinov, 2019, Oncogenic KRas mobility in the membrane and signaling response, Semin Cancer Biol, 54, 109, 10.1016/j.semcancer.2018.02.009

Chavan, 2015, High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site, Biophys J, 109, 2602, 10.1016/j.bpj.2015.09.034

Jang, 2016, The higher level of complexity of K-Ras4B activation at the membrane, FASEB J, 30, 1643, 10.1096/fj.15-279091

Terai, 2006, The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf, EMBO J, 25, 3556, 10.1038/sj.emboj.7601241

Chong, 2003, Regulation of Raf through phosphorylation and N terminus-C terminus interaction, J Biol Chem, 278, 36269, 10.1074/jbc.M212803200

Bruder, 1992, Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase, Genes Dev, 6, 545, 10.1101/gad.6.4.545

Fukui, 1987, Molecular cloning and characterization of an activated human c-raf-1 gene, Mol Cell Biol, 7, 1776, 10.1128/MCB.7.5.1776

Heidecker, 1990, Mutational activation of c-raf-1 and definition of the minimal transforming sequence, Mol Cell Biol, 10, 2503, 10.1128/MCB.10.6.2503

Ishikawa, 1988, Identification of a transforming activity suppressing sequence in the c-raf oncogene, Oncogene, 3, 653

Ishikawa, 1986, Activation of rat c-raf during transfection of hepatocellular carcinoma DNA, Proc Natl Acad Sci USA, 83, 3209, 10.1073/pnas.83.10.3209

Molders, 1985, Integration of transfected LTR sequences into the c-raf proto-oncogene: activation by promoter insertion, EMBO J, 4, 693, 10.1002/j.1460-2075.1985.tb03685.x

Schultz, 1988, Identification and characterization of c-raf phosphoproteins in transformed murine cells, Oncogene, 2, 187

Stanton, 1987, Activation of human raf transforming genes by deletion of normal amino-terminal coding sequences, Mol Cell Biol, 7, 1171, 10.1128/MCB.7.3.1171

Stanton, 1989, Definition of the human raf amino-terminal regulatory region by deletion mutagenesis, Mol Cell Biol, 9, 639, 10.1128/MCB.9.2.639

Cutler, 1998, Autoregulation of the Raf-1 serine/threonine kinase, Proc Natl Acad Sci USA, 95, 9214, 10.1073/pnas.95.16.9214

Tran, 2003, Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition, J Biol Chem, 278, 11221, 10.1074/jbc.M210318200

Tran, 2005, B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms, J Biol Chem, 280, 16244, 10.1074/jbc.M501185200

Zhang, 2000, Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601, EMBO J, 19, 5429, 10.1093/emboj/19.20.5429

Zhang, 2001, Regulation of the Raf kinase by phosphorylation, Exp Lung Res, 27, 269, 10.1080/019021401300054046

Wan, 2004, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF, Cell, 116, 855, 10.1016/S0092-8674(04)00215-6

Kohler, 2016, Activation loop phosphorylation regulates B-Raf in vivo and transformation by B-Raf mutants, EMBO J, 35, 143, 10.15252/embj.201592097

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

Cook, 1993, Inhibition by cAMP of Ras-dependent activation of Raf, Science, 262, 1069, 10.1126/science.7694367

Dhillon, 2002, Regulation of Raf-1 activation and signalling by dephosphorylation, EMBO J, 21, 64, 10.1093/emboj/21.1.64

Wu, 1993, Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate, Science, 262, 1065, 10.1126/science.7694366

Rommel, 1999, Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt, Science, 286, 1738, 10.1126/science.286.5445.1738

Zimmermann, 1999, Phosphorylation and regulation of Raf by Akt (protein kinase B), Science, 286, 1741, 10.1126/science.286.5445.1741

Dhillon, 2002, Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259, Mol Cell Biol, 22, 3237, 10.1128/MCB.22.10.3237-3246.2002

Light, 2002, 14–3-3 antagonizes Ras-mediated Raf-1 recruitment to the plasma membrane to maintain signaling fidelity, Mol Cell Biol, 22, 4984, 10.1128/MCB.22.14.4984-4996.2002

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

Tzivion, 1998, A dimeric 14–3-3 protein is an essential cofactor for Raf kinase activity, Nature, 394, 88, 10.1038/27938

Herrmann, 1996, Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor, J Biol Chem, 271, 6794, 10.1074/jbc.271.12.6794

Li, 2018, Raf-1 Cysteine-rich domain increases the affinity of K-Ras/Raf at the membrane, promoting MAPK signaling, Structure, 26, 513, 10.1016/j.str.2018.01.011

Li, 2018, A “Tug of War” maintains a dynamic protein-membrane complex: molecular dynamics simulations of C-Raf RBD-CRD bound to K-Ras4B at an anionic membrane, ACS Cent Sci, 4, 298, 10.1021/acscentsci.7b00593

Travers, 2018, Molecular recognition of RAS/RAF complex at the membrane: role of RAF cysteine-rich domain, Sci Rep, 8, 8461, 10.1038/s41598-018-26832-4

Improta-Brears, 1999, Mutational analysis of Raf-1 cysteine rich domain: requirement for a cluster of basic aminoacids for interaction with phosphatidylserine, Mol Cell Biochem, 198, 171, 10.1023/A:1006981411691

Thapar, 2004, NMR characterization of full-length farnesylated and non-farnesylated H-Ras and its implications for Raf activation, J Mol Biol, 343, 1391, 10.1016/j.jmb.2004.08.106

Li, 2017, Computational modeling reveals that signaling lipids modulate the orientation of K-Ras4A at the membrane reflecting protein topology, Structure, 25, 679, 10.1016/j.str.2017.02.007

Abankwa, 2010, Ras membrane orientation and nanodomain localization generate isoform diversity, Proc Natl Acad Sci USA, 107, 1130, 10.1073/pnas.0903907107

Gorfe, 2007, Structure and dynamics of the full-length lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer, J Med Chem, 50, 674, 10.1021/jm061053f

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

Rommel, 1996, Activated Ras displaces 14–3-3 protein from the amino terminus of c-Raf-1, Oncogene, 12, 609

Abraham, 2000, Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation, J Biol Chem, 275, 22300, 10.1074/jbc.M003259200

Jaumot, 2001, Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14–3-3 interactions, Oncogene, 20, 3949, 10.1038/sj.onc.1204526

Ory, 2003, Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14–3-3 binding sites, Curr Biol, 13, 1356, 10.1016/S0960-9822(03)00535-9

Matallanas, 2011, Raf family kinases: old dogs have learned new tricks, Genes Cancer, 2, 232, 10.1177/1947601911407323

Dumaz, 2003, Protein kinase A blocks Raf-1 activity by stimulating 14–3-3 binding and blocking Raf-1 interaction with Ras, J Biol Chem, 278, 29819, 10.1074/jbc.C300182200

Molzan, 2012, Synergistic binding of the phosphorylated S233- and S259-binding sites of C-RAF to one 14–3-3zeta dimer, J Mol Biol, 423, 486, 10.1016/j.jmb.2012.08.009

2018, MEK Binding to KSR promotes allosteric activation of BRAF, Cancer Discov, 8, 385, 10.1158/2159-8290.CD-RW2018-033

Lavoie, 2018, MEK drives BRAF activation through allosteric control of KSR proteins, Nature, 554, 549, 10.1038/nature25478

Ren, 2007, IQGAP1 modulates activation of B-Raf, Proc Natl Acad Sci USA, 104, 10465, 10.1073/pnas.0611308104

Stewart, 1999, Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization, Mol Cell Biol, 19, 5523, 10.1128/MCB.19.8.5523

Shalom-Feuerstein, 2008, K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3, Cancer Res, 68, 6608, 10.1158/0008-5472.CAN-08-1117

White, 2012, IQGAP1 and its binding proteins control diverse biological functions, Cell Signal, 24, 826, 10.1016/j.cellsig.2011.12.005

Nussinov, 2019, Is Nanoclustering essential for all oncogenic KRas pathways? Can it explain why wild-type KRas can inhibit its oncogenic variant, Semin Cancer Biol, 54, 114, 10.1016/j.semcancer.2018.01.002

Santos, 2018, The RAS-ERK pathway: a route for couples, Sci Signal, 11, eaav0917, 10.1126/scisignal.aav0917

Nussinov, 2014, Dynamic multiprotein assemblies shape the spatial structure of cell signaling, Prog Biophys Mol Biol, 116, 158, 10.1016/j.pbiomolbio.2014.07.002

Avruch, 2009, Rassf family of tumor suppressor polypeptides, J Biol Chem, 284, 11001, 10.1074/jbc.R800073200

Avruch, 2012, Protein kinases of the Hippo pathway: regulation and substrates, Semin Cell Dev Biol, 23, 770, 10.1016/j.semcdb.2012.07.002

Donninger, 2016, Ras signaling through RASSF proteins, Semin Cell Dev Biol, 58, 86, 10.1016/j.semcdb.2016.06.007

Nussinov, 2017, Intrinsic protein disorder in oncogenic KRAS signaling, Cell Mol Life Sci, 74, 3245, 10.1007/s00018-017-2564-3

Richter, 2009, The RASSF proteins in cancer; from epigenetic silencing to functional characterization, Biochim Biophys Acta, 1796, 114, 10.1016/j.bbcan.2009.03.004

Fallahi, 2016, The MST/hippo pathway and cell death: a non-canonical affair, Genes, 7, E28, 10.3390/genes7060028

Huang, 2007, The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations, Science, 318, 1744, 10.1126/science.1150799

Makbul, 2013, Structural and thermodynamic characterization of Nore1-SARAH: a small, helical module important in signal transduction networks, Biochemistry, 52, 1045, 10.1021/bi3014642

Stieglitz, 2008, Novel type of Ras effector interaction established between tumour suppressor NORE1A and Ras switch II, EMBO J, 27, 1995, 10.1038/emboj.2008.125

Kumar, 2000, Folding and binding cascades: dynamic landscapes and population shifts, Protein Sci, 9, 10, 10.1110/ps.9.1.10

Liu, 2017, Energetic redistribution in allostery to execute protein function, Proc Natl Acad Sci USA, 114, 7480, 10.1073/pnas.1709071114

Ma, 1999, Folding funnels and binding mechanisms, Protein Eng, 12, 713, 10.1093/protein/12.9.713

Nussinov, 2011, Allo-network drugs: harnessing allostery in cellular networks, Trends Pharmacol Sci, 32, 686, 10.1016/j.tips.2011.08.004

Nussinov, 2014, A second molecular biology revolution? The energy landscapes of biomolecular function, Phys Chem Chem Phys, 16, 6321, 10.1039/c4cp90027h

Tsai, 2009, Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms, Mol Biosyst, 5, 207, 10.1039/b819720b

Tsai, 1999, Folding funnels, binding funnels, and protein function, Protein Sci, 8, 1181, 10.1110/ps.8.6.1181

Tsai, 1999, Folding and binding cascades: shifts in energy landscapes, Proc Natl Acad Sci USA, 96, 9970, 10.1073/pnas.96.18.9970

Wei, 2016, Protein ensembles: how does nature harness thermodynamic fluctuations for life? the diverse functional roles of conformational ensembles in the cell, Chem Rev, 116, 6516, 10.1021/acs.chemrev.5b00562

Tsai, 2008, Allostery: absence of a change in shape does not imply that allostery is not at play, J Mol Biol, 378, 1, 10.1016/j.jmb.2008.02.034

Yang, 2017, Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40, Nature, 552, 368, 10.1038/nature25023