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SRChing for the substrates of Src

Oncogene volume 33, pages 4537–4547 (2014)Cite this article

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Abstract

By the mid 1980’s, it was clear that the transforming activity of oncogenic Src was linked to the activity of its tyrosine kinase domain and attention turned to identifying substrates, the putative next level of control in the pathway to transformation. Among the first to recognize the potential of phosphotyrosine-specific antibodies, Parsons and colleagues launched a risky shotgun-based approach that led ultimately to the cDNA cloning and functional characterization of many of today’s best-known Src substrates (for example, p85-Cortactin, p110-AFAP1, p130Cas, p125FAK and p120-catenin). Two decades and over 6000 citations later, the original goals of the project may be seen as secondary to the enormous impact of these protein substrates in many areas of biology. At the request of the editors, this review is not restricted to the current status of the substrates, but reflects also on the anatomy of the project itself and some of the challenges and decisions encountered along the way.

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References

  1. Vogt PK . Retroviral oncogenes: a historical primer. Nat Rev Cancer. 2012; 12: 639–648.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Hunter T, Sefton BM . Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci USA. 1980; 77: 1311–1315.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pawson T, Kung TH, Martin GS . Structure and phosphorylation of the Fujinami sarcoma virus gene product. J Virol 1981; 40: 665–672.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Witte ON, Dasgupta A, Baltimore D . Abelson murine leukaemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature 1980; 283: 826–831.

    CAS  PubMed  Google Scholar 

  5. Schaller MD, Bouton AH, Flynn DC, Parsons JT . Identification and characterization of novel substrates for protein tyrosine kinases. Prog Nucleic Acid Res Mol Biol 1993; 44: 205–227.

    CAS  PubMed  Google Scholar 

  6. Kamps MP, Sefton BM . Identification of multiple novel polypeptide substrates of the v-src, v-yes, v-fps, v-ros, and v-erb-B oncogenic tyrosine protein kinases utilizing antisera against phosphotyrosine. Oncogene 1988; 2: 305–315.

    CAS  PubMed  Google Scholar 

  7. Kanner SB, Reynolds AB, Parsons JT . Immunoaffinity purification of tyrosine-phosphorylated cellular proteins. J Immunol Methods 1989; 120: 115–124.

    CAS  PubMed  Google Scholar 

  8. Kanner SB, Reynolds AB, Vines RR, Parsons JT . Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases. Proc Natl Acad Sci USA. 1990; 87: 3328–3332.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu H, Parsons JT . Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. J Cell Biol 1993; 120: 1417–1426.

    CAS  PubMed  Google Scholar 

  10. Zhan X, Hu X, Friesel R, Maciag T . Long term growth factor exposure and differential tyrosine phosphorylation are required for DNA synthesis in BALB/c 3T3 cells. J Biol Chem 1993; 268: 9611–9620.

    CAS  PubMed  Google Scholar 

  11. Wu H, Reynolds AB, Kanner SB, Vines RR, Parsons JT . Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol Cell Biol 1991; 11: 5113–5124.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schuuring E, Verhoeven E, Mooi WJ, Michalides RJ . Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene 1992; 7: 355–361.

    CAS  PubMed  Google Scholar 

  13. Uruno T, Liu J, Zhang P, Fan Y, Egile C, Li R et al. Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat Cell Biol 2001; 3: 259–266.

    CAS  PubMed  Google Scholar 

  14. Weaver AM, Heuser JE, Karginov AV, Lee WL, Parsons JT, Cooper JA . Interaction of cortactin and N-WASp with Arp2/3 complex. Curr Biol 2002; 12: 1270–1278.

    CAS  PubMed  Google Scholar 

  15. Weed SA, Karginov AV, Schafer DA, Weaver AM, Kinley AW, Cooper JA et al. Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex. J Cell Biol 2000; 151: 29–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kowalski JR, Egile C, Gil S, Snapper SB, Li R, Thomas SM . Cortactin regulates cell migration through activation of N-WASP. J Cell Sci 2005; 118 (Pt 1): 79–87.

    CAS  PubMed  Google Scholar 

  17. Martinez-Quiles N, Ho HY, Kirschner MW, Ramesh N, Geha RS . Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol Cell Biol 2004; 24: 5269–5280.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Weaver AM, Karginov AV, Kinley AW, Weed SA, Li Y, Parsons JT et al. Cortactin promotes and stabilizes Arp2/3-induced actin filament network formation. Curr Biol 2001; 11: 370–374.

    CAS  PubMed  Google Scholar 

  19. Bryce NS, Clark ES, Leysath JL, Currie JD, Webb DJ, Weaver AM . Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr Biol 2005; 15: 1276–1285.

    CAS  PubMed  Google Scholar 

  20. Boguslavsky S, Grosheva I, Landau E, Shtutman M, Cohen M, Arnold K et al. p120 catenin regulates lamellipodial dynamics and cell adhesion in cooperation with cortactin. Proc Natl Acad Sci USA. 2007; 104: 10882–10887.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tehrani S, Tomasevic N, Weed S, Sakowicz R, Cooper JA . Src phosphorylation of cortactin enhances actin assembly. Proc Natl Acad Sci USA. 2007; 104: 11933–11938.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Oser M, Yamaguchi H, Mader CC, Bravo-Cordero JJ, Arias M, Chen X et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol 2009; 186: 571–587.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Oser M, Mader CC, Gil-Henn H, Magalhaes M, Bravo-Cordero JJ, Koleske AJ et al. Specific tyrosine phosphorylation sites on cortactin regulate Nck1-dependent actin polymerization in invadopodia. J Cell Sci 2010; 123 (Pt 21): 3662–3673.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Murphy DA, Courtneidge SA . The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 2011; 12: 413–426.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Linder S, Wiesner C, Himmel M . Degrading devices: invadosomes in proteolytic cell invasion. Ann Rev Cell Dev Biol 2011; 27: 185–211.

    CAS  Google Scholar 

  26. Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller SC . Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res 2006; 66: 3034–3043.

    CAS  PubMed  Google Scholar 

  27. Magalhaes MA, Larson DR, Mader CC, Bravo-Cordero JJ, Gil-Henn H, Oser M et al. Cortactin phosphorylation regulates cell invasion through a pH-dependent pathway. J Cell Biol 2011; 195: 903–920.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu D, Zhang H, Blanpied TA, Smith E, Zhan X . Cortactin is implicated in murine zygotic development. Exp Cell Res 2010; 316: 848–858.

    CAS  PubMed  Google Scholar 

  29. Schnoor M, Lai FP, Zarbock A, Klaver R, Polaschegg C, Schulte D et al. Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo. J Exp Med 2011; 208: 1721–1735.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilkerson PM, Reis-Filho JS . The 11q13-q14 amplicon: clinicopathological correlations and potential drivers. Genes Chromosomes Cancer 2013; 52: 333–355.

    CAS  PubMed  Google Scholar 

  31. Rodrigo JP, Garcia LA, Ramos S, Lazo PS, Suarez C . EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res 2000; 6: 3177–3182.

    CAS  PubMed  Google Scholar 

  32. Rodrigo JP, Garcia-Carracedo D, Garcia LA, Menendez S, Allonca E, Gonzalez MV et al. Distinctive clinicopathological associations of amplification of the cortactin gene at 11q13 in head and neck squamous cell carcinomas. J Pathol 2009; 217: 516–523.

    CAS  PubMed  Google Scholar 

  33. Rodrigo JP, Alvarez-Alija G, Menendez ST, Mancebo G, Allonca E, Garcia-Carracedo D et al. Cortactin and focal adhesion kinase as predictors of cancer risk in patients with laryngeal premalignancy. Cancer Prevention Res 2011; 4: 1333–1341.

    CAS  Google Scholar 

  34. Rothschild BL, Shim AH, Ammer AG, Kelley LC, Irby KB, Head JA et al. Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Cancer Res 2006; 66: 8017–8025.

    CAS  PubMed  Google Scholar 

  35. Clark ES, Whigham AS, Yarbrough WG, Weaver AM . Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res 2007; 67: 4227–4235.

    CAS  PubMed  Google Scholar 

  36. Timpson P, Wilson AS, Lehrbach GM, Sutherland RL, Musgrove EA, Daly RJ . Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib. Cancer Res 2007; 67: 9304–9314.

    CAS  PubMed  Google Scholar 

  37. Eke I, Deuse Y, Hehlgans S, Gurtner K, Krause M, Baumann M et al. beta(1)Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest 2012; 122: 1529–1540.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kanner SB, Reynolds AB, Wang HC, Vines RR, Parsons JT . The SH2 and SH3 domains of pp60src direct stable association with tyrosine phosphorylated proteins p130 and p110. EMBO J. 1991; 10: 1689–1698.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu W, Harrison SC, Eck MJ . Three-dimensional structure of the tyrosine kinase c-Src. Nature 1997; 385: 595–602.

    CAS  PubMed  Google Scholar 

  40. Snyder BN, Cho Y, Qian Y, Coad JE, Flynn DC, Cunnick JM . AFAP1L1 is a novel adaptor protein of the AFAP family that interacts with cortactin and localizes to invadosomes. Eur J Cell Biol 2011; 90: 376–389.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Flynn DC, Koay TC, Humphries CG, Guappone AC . AFAP-120. A variant form of the Src SH2/SH3-binding partner AFAP-110 is detected in brain and contains a novel internal sequence which binds to a 67-kDa protein. J Biol Chem 1995; 270: 3894–3899.

    CAS  PubMed  Google Scholar 

  42. Flynn DC, Leu TH, Reynolds AB, Parsons JT . Identification and sequence analysis of cDNAs encoding a 110-kilodalton actin filament-associated pp60src substrate. Mol Cell Biol 1993; 13: 7892–7900.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Qian Y, Baisden JM, Zot HG, Van Winkle WB, Flynn DC . The carboxy terminus of AFAP-110 modulates direct interactions with actin filaments and regulates its ability to alter actin filament integrity and induce lamellipodia formation. Exp Cell Res 2000; 255: 102–113.

    CAS  PubMed  Google Scholar 

  44. Qian Y, Gatesman AS, Baisden JM, Zot HG, Cherezova L, Qazi I et al. Analysis of the role of the leucine zipper motif in regulating the ability of AFAP-110 to alter actin filament integrity. J Cell Biochem 2004; 91: 602–620.

    CAS  PubMed  Google Scholar 

  45. Summy JM, Guappone AC, Sudol M, Flynn DC . The SH3 and SH2 domains are capable of directing specificity in protein interactions between the non-receptor tyrosine kinases cSrc and cYes. Oncogene 2000; 19: 155–160.

    CAS  PubMed  Google Scholar 

  46. Baisden JM, Qian Y, Zot HM, Flynn DC . The actin filament-associated protein AFAP-110 is an adaptor protein that modulates changes in actin filament integrity. Oncogene 2001; 20: 6435–6447.

    CAS  PubMed  Google Scholar 

  47. Bruce-Staskal PJ, Bouton AH . PKC-dependent activation of FAK and src induces tyrosine phosphorylation of Cas and formation of Cas-Crk complexes. Exp Cell Res 2001; 264: 296–306.

    CAS  PubMed  Google Scholar 

  48. Brandt D, Gimona M, Hillmann M, Haller H, Mischak H . Protein kinase C induces actin reorganization via a Src- and Rho-dependent pathway. J Biol Chem 2002; 277: 20903–20910.

    CAS  PubMed  Google Scholar 

  49. Gatesman A, Walker VG, Baisden JM, Weed SA, Flynn DC . Protein kinase Calpha activates c-Src and induces podosome formation via AFAP-110. Mol Cell Biol 2004; 24: 7578–7597.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Walker VG, Ammer A, Cao Z, Clump AC, Jiang B-H, Kelley LC et al. PI3K activation is required for PMA-directed activation of cSrc by AFAP-110. Am J Physiol Cell Physiol 2007; 293: 119–132.

    Google Scholar 

  51. Zhang J, Park SI, Artime MC, Summy JM, Shah AN, Bomser JA et al. AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J Clin Invest 2007; 117: 2962–2973.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Berwanger B, Hartmann O, Bergmann E, Bernard S, Nielsen D, Krause M et al. Loss of a FYN-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma. Cancer Cell 2002; 2: 377–386.

    CAS  PubMed  Google Scholar 

  53. Reynolds AB, Roesel DJ, Kanner SB, Parsons JT . Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene. Mol Cell Biol 1989; 9: 629–638.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sakai R, Iwamatsu A, Hirano N, Ogawa S, Tanaka T, Mano H et al. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994; 13: 3748–3756.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Nakamoto T, Sakai R, Ozawa K, Yazaki Y, Hirai H . Direct binding of C-terminal region of p130Cas to SH2 and SH3 domains of Src kinase. J Biol Chem 1996; 271: 8959–8965.

    CAS  PubMed  Google Scholar 

  56. Pellicena P, Stowell KR, Miller WT . Enhanced phosphorylation of Src family kinase substrates containing SH2 domain binding sites. J Biol Chem 1998; 273: 15325–15328.

    CAS  PubMed  Google Scholar 

  57. Pellicena P, Miller WT . Processive phosphorylation of p130Cas by Src depends on SH3-polyproline interactions. J Biol Chem 2001; 276: 28190–28196.

    CAS  PubMed  Google Scholar 

  58. Guappone AC, Flynn DC . The integrity of the SH3 binding motif of AFAP-110 is required to facilitate tyrosine phosphorylation by, and stable complex formation with, Src. Mol Cell Biochem 1997; 175: 243–252.

    CAS  PubMed  Google Scholar 

  59. Guappone AC, Weimer T, Flynn DC . Formation of a stable src-AFAP-110 complex through either an amino-terminal or a carboxy-terminal SH2-binding motif. Mol Carcinogen 1998; 22: 110–119.

    CAS  Google Scholar 

  60. Sicheri F, Moarefi I, Kuriyan J . Crystal structure of the Src family tyrosine kinase Hck. Nature 1997; 385: 602–609.

    CAS  PubMed  Google Scholar 

  61. Williams JC, Weijland A, Gonfloni S, Thompson A, Courtneidge SA, Superti-Furga G et al. The 2.35 a crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions. J Mol Biol 1997; 274: 757–775.

    CAS  PubMed  Google Scholar 

  62. Burnham MR, Bruce-Staskal PJ, Harte MT, Weidow CL, Ma A, Weed SA et al. Regulation of c-SRC activity and function by the adapter protein CAS. Mol Cell Biol 2000; 20: 5865–5878.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bouton AH, Riggins RB, Bruce-Staskal PJ . Functions of the adapter protein Cas: signal convergence and the determination of cellular responses. Oncogene 2001; 20: 6448–6458.

    CAS  PubMed  Google Scholar 

  64. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P . Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 2010; 10: 858–870.

    CAS  PubMed  Google Scholar 

  65. Tikhmyanova N, Little JL, Golemis EA . CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci 2010; 67: 1025–1048.

    CAS  PubMed  Google Scholar 

  66. Guerrero MS, Parsons JT, Bouton AH . Cas and NEDD9 contribute to tumor progression through dynamic regulation of the cytoskeleton. Genes Cancer 2012; 3: 371–381.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Nojima Y, Morino N, Mimura T, Hamasaki K, Furuya H, Sakai R et al. Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, a Src homology 3-containing molecule having multiple Src homology 2-binding motifs. J Biol Chem 1995; 270: 15398–15402.

    CAS  PubMed  Google Scholar 

  68. Harte MT, Hildebrand JD, Burnham MR, Bouton AH, Parsons JT . p130Cas, a substrate associated with v-Src and v-Crk, localizes to focal adhesions and binds to focal adhesion kinase. J Biol Chem 1996; 271: 13649–13655.

    CAS  PubMed  Google Scholar 

  69. Honda H, Nakamoto T, Sakai R, Hirai H . p130(Cas), an assembling molecule of actin filaments, promotes cell movement, cell migration, and cell spreading in fibroblasts. Biochem Biophys Res Commun 1999; 262: 25–30.

    CAS  PubMed  Google Scholar 

  70. Harte MT, Macklem M, Weidow CL, Parsons JT, Bouton AH . Identification of two focal adhesion targeting sequences in the adapter molecule p130(Cas). Biochim Biophys Acta 2000; 1499: 34–48.

    CAS  PubMed  Google Scholar 

  71. Meenderink LM, Ryzhova LM, Donato DM, Gochberg DF, Kaverina I, Hanks SK . P130Cas Src-binding and substrate domains have distinct roles in sustaining focal adhesion disassembly and promoting cell migration. PLoS One 2010; 5: e13412.

    PubMed  PubMed Central  Google Scholar 

  72. Nakamoto T, Sakai R, Honda H, Ogawa S, Ueno H, Suzuki T et al. Requirements for localization of p130cas to focal adhesions. Mol Cell Biol 1997; 17: 3884–3897.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA . CAS/Crk coupling serves as a ‘molecular switch’ for induction of cell migration. J Cell Biol 1998; 140: 961–972.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Cho SY, Klemke RL . Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J Cell Biol 2000; 149: 223–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cho SY, Klemke RL . Purification of pseudopodia from polarized cells reveals redistribution and activation of Rac through assembly of a CAS/Crk scaffold. J Cell Biol 2002; 156: 725–736.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S et al. Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell 2006; 127: 1015–1026.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kim W, Kook S, Kim DJ, Teodorof C, Song WK . The 31-kDa caspase-generated cleavage product of p130cas functions as a transcriptional repressor of E2A in apoptotic cells. J Biol Chem 2004; 279: 8333–8342.

    CAS  PubMed  Google Scholar 

  78. Wei L, Yang Y, Zhang X, Yu Q . Cleavage of p130Cas in anoikis. J Cell Biochem 2004; 91: 325–335.

    CAS  PubMed  Google Scholar 

  79. Casamassima A, Rozengurt E . Tyrosine phosphorylation of p130(cas) by bombesin, lysophosphatidic acid, phorbol esters, and platelet-derived growth factor. Signaling pathways and formation of a p130(cas)-Crk complex. J Biol Chem 1997; 272: 9363–9370.

    CAS  PubMed  Google Scholar 

  80. Casamassima A, Rozengurt E . Insulin-like growth factor I stimulates tyrosine phosphorylation of p130(Cas), focal adhesion kinase, and paxillin. Role of phosphatidylinositol 3'-kinase and formation of a p130(Cas).Crk complex. J Biol Chem 1998; 273: 26149–26156.

    CAS  PubMed  Google Scholar 

  81. Yamakita Y, Totsukawa G, Yamashiro S, Fry D, Zhang X, Hanks SK et al. Dissociation of FAK/p130(CAS)/c-Src complex during mitosis: role of mitosis-specific serine phosphorylation of FAK. J Cell Biol 1999; 144: 315–324.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res 2006; 66: 4672–4680.

    CAS  PubMed  Google Scholar 

  83. van der Flier S, Brinkman A, Look MP, Kok EM, Meijer-van Gelder ME, Klijn JG et al. Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment. J Natl Cancer Inst 2000; 92: 120–127.

    CAS  PubMed  Google Scholar 

  84. Brinkman A, van der Flier S, Kok EM, Dorssers LC . BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells. J Natl Cancer Inst 2000; 92: 112–120.

    CAS  PubMed  Google Scholar 

  85. Dorssers LC, Grebenchtchikov N, Brinkman A, Look MP, van Broekhoven SP, de Jong D et al. The prognostic value of BCAR1 in patients with primary breast cancer. Clin Cancer Res 2004; 10 (18 Pt 1): 6194–6202.

    CAS  PubMed  Google Scholar 

  86. Fromont G, Vallancien G, Validire P, Levillain P, Cussenot O . BCAR1 expression in prostate cancer: association with 16q23 LOH status, tumor progression and EGFR/KAI1 staining. Prostate 2007; 67: 268–273.

    PubMed  Google Scholar 

  87. Nick AM, Stone RL, Armaiz-Pena G, Ozpolat B, Tekedereli I, Graybill WS et al. Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. J Natl Cancer Inst 2011; 103: 1596–1612.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Huang W, Deng B, Wang RW, Tan QY, He Y, Jiang YG et al. BCAR1 protein plays important roles in carcinogenesis and predicts poor prognosis in non-small-cell lung cancer. PLoS One 2012; 7: e36124.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Riggins RB, Thomas KS, Ta HQ, Wen J, Davis RJ, Schuh NR et al. Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res 2006; 66: 7007–7015.

    CAS  PubMed  Google Scholar 

  90. Ta HQ, Thomas KS, Schrecengost RS, Bouton AH . A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. Cancer Res 2008; 68: 8796–8804.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Riggins RB, Quilliam LA, Bouton AH . Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. J Biol Chem 2003; 278: 28264–28273.

    CAS  PubMed  Google Scholar 

  92. Schuh NR, Guerrero MS, Schrecengost RS, Bouton AH . BCAR3 regulates Src/p130 Cas association, Src kinase activity, and breast cancer adhesion signaling. J Biol Chem 2010; 285: 2309–2317.

    CAS  PubMed  Google Scholar 

  93. Reynolds AB, Vila J, Lansing TJ, Potts WM, Weber MJ, Parsons JT . Activation of the oncogenic potential of the avian cellular src protein by specific structural alteration of the carboxy terminus. EMBO J 1987; 6: 2359–2364.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Guan JL, Trevithick JE, Hynes RO . Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Reg 1991; 2: 951–964.

    CAS  Google Scholar 

  95. Kornberg LJ, Earp HS, Turner CE, Prockop C, Juliano RL . Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci USA 1991; 88: 8392–8396.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Golden A, Brugge JS, Shattil SJ . Role of platelet membrane glycoprotein IIb-IIIa in agonist-induced tyrosine phosphorylation of platelet proteins. J Cell Biol 1990; 111 (6 Pt 2): 3117–3127.

    CAS  PubMed  Google Scholar 

  97. Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT . pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 1992; 89: 5192–5196.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Parsons JT . Focal adhesion kinase: the first ten years. J Cell Sci 2003; 116 (Pt 8): 1409–1416.

    CAS  PubMed  Google Scholar 

  99. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT . Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 1994; 14: 1680–1688.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ren XD, Kiosses WB, Sieg DJ, Otey CA, Schlaepfer DD, Schwartz MA . Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci 2000; 113 (Pt 20): 3673–3678.

    CAS  PubMed  Google Scholar 

  101. Owen KA, Pixley FJ, Thomas KS, Vicente-Manzanares M, Ray BJ, Horwitz AF et al. Regulation of lamellipodial persistence, adhesion turnover, and motility in macrophages by focal adhesion kinase. J Cell Biol 2007; 179: 1275–1287.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Webb DJ, Donais K, Whitmore LA, Thomas SM, Turner CE, Parsons JT et al. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat Cell Biol 2004; 6: 154–161.

    CAS  PubMed  Google Scholar 

  103. Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA . Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 2002; 420: 89–93.

    CAS  PubMed  Google Scholar 

  104. Hildebrand JD, Taylor JM, Parsons JT . An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase. Mol Cell Biol 1996; 16: 3169–3178.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Iwanicki MP, Vomastek T, Tilghman RW, Martin KH, Banerjee J, Wedegaertner PB et al. FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts. J Cell Sci 2008; 121 (Pt 6): 895–905.

    CAS  PubMed  Google Scholar 

  106. Lim Y, Lim S-T, Tomar A, Gardel M, Bernard-Trifilo JA, Chen XL et al. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol 2008; 180: 187–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ren XR, Du QS, Huang YZ, Ao SZ, Mei L, Xiong WC . Regulation of CDC42 GTPase by proline-rich tyrosine kinase 2 interacting with PSGAP, a novel pleckstrin homology and Src homology 3 domain containing rhoGAP protein. J Cell Biol 2001; 152: 971–984.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Tomar A, Lim S-T, Lim Y, Schlaepfer DD . A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells. J Cell Sci 2009; 122 (Pt 11): 1852–1862.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL . Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem 1995; 270: 16995–16999.

    CAS  PubMed  Google Scholar 

  110. Hildebrand JD, Schaller MD, Parsons JT . Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase. Mol Biol Cell 1995; 6: 637–647.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Glenney JR Jr, Zokas L . Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton. J Cell Biol 1989; 108: 2401–2408.

    CAS  PubMed  Google Scholar 

  112. Lawson C, Lim S-T, Uryu S, Chen XL, Calderwood DA, Schlaepfer DD . FAK promotes recruitment of talin to nascent adhesions to control cell motility. J Cell Biol 2012; 196: 223–232.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Nayal A, Webb DJ, Horwitz AF . Talin: an emerging focal point of adhesion dynamics. Curr Opin Cell Biol 2004; 16: 94–98.

    CAS  PubMed  Google Scholar 

  114. Franco SJ, Rodgers MA, Perrin BJ, Han J, Bennin DA, Critchley DR et al. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol 2004; 6: 977–983.

    CAS  PubMed  Google Scholar 

  115. Tomar A, Lawson C, Ghassemian M, Schlaepfer DD . Cortactin as a target for FAK in the regulation of focal adhesion dynamics. PLoS One 2012; 7: 8 e44041.

    Google Scholar 

  116. Ezratty EJ, Partridge MA, Gundersen GG . Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat Cell Biol 2005; 7: 581–590.

    CAS  PubMed  Google Scholar 

  117. Wang Y, Cao H, Chen J, McNiven MA . A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active Src. Mol Biol Cell 2011; 22: 1529–1538.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Beggs HE, Schahin-Reed D, Zang K, Goebbels S, Nave KA, Gorski J et al. FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 2003; 40: 501–514.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Midwood KS, Schwarzbauer JE . Tenascin-C modulates matrix contraction via focal adhesion kinase- and Rho-mediated signaling pathways. Mol Biol Cell 2002; 13: 3601–3613.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP et al. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 2001; 61: 7079–7090.

    CAS  PubMed  Google Scholar 

  121. Wu X, Gan B, Yoo Y, Guan J-L . FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. Dev Cell 2005; 9: 185–196.

    CAS  PubMed  Google Scholar 

  122. Pan Y-R, Chen C-L, Chen H-C . FAK is required for the assembly of podosome rosettes. J Cell Biol 2011; 195: 113–129.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Wang Y, McNiven MA . Invasive matrix degradation at focal adhesions occurs via protease recruitment by a FAK-p130Cas complex. J Cell Biol 2012; 196: 375–385.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Klein EA, Yin L, Kothapalli D, Castagnino P, Byfield FJ, Xu T et al. Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol 2009; 19: 1511–1518.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Parekh A, Weaver AM . Regulation of cancer invasiveness by the physical extracellular matrix environment. Cell Adh Migr 2009; 3: 288–292.

    PubMed  PubMed Central  Google Scholar 

  126. Provenzano PP, Inman DR, Eliceiri KW, Keely PJ . Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 2009; 28: 4326–4343.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Playford MP, Vadali K, Cai X, Burridge K, Schaller MD . Focal adhesion kinase regulates cell-cell contact formation in epithelial cells via modulation of Rho. Exp Cell Res 2008; 314: 3187–3197.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Yano H, Mazaki Y, Kurokawa K, Hanks SK, Matsuda M, Sabe H . Roles played by a subset of integrin signaling molecules in cadherin-based cell-cell adhesion. J Cell Biol 2004; 166: 283–295.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol 2002; 4: 632–638.

    CAS  PubMed  Google Scholar 

  130. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995; 377: 539–544.

    CAS  PubMed  Google Scholar 

  131. Furuta Y, Ilic D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S . Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene 1995; 11: 1989–1995.

    CAS  PubMed  Google Scholar 

  132. Braren R, Hu H, Kim YH, Beggs HE, Reichardt LF, Wang R . Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation. J Cell Biol 2006; 172: 151–162.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P et al. Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 2005; 169: 941–952.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hakim ZS, DiMichele LA, Doherty JT, Homeister JW, Beggs HE, Reichardt LF et al. Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment. Mol Cell Biol 2007; 27: 5352–5364.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Vallejo-Illarramendi A, Zang K, Reichardt LF . Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development. J Clin Invest 2009; 119: 2218–2230.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Rico B, Beggs HE, Schahin-Reed D, Kimes N, Schmidt A, Reichardt LF . Control of axonal branching and synapse formation by focal adhesion kinase. Nat Neurosci 2004; 7: 1059–1069.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Forrest AD, Beggs HE, Reichardt LF, Dupree JL, Colello RJ, Fuss B . Focal adhesion kinase (FAK): a regulator of CNS myelination. J Neurosci Res 2009; 87: 3456–3464.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Nagy T, Wei H, Shen TL, Peng X, Liang CC, Gan B et al. Mammary epithelial-specific deletion of the focal adhesion kinase gene leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland. J Biol Chem 2007; 282: 31766–31776.

    CAS  PubMed  Google Scholar 

  139. Peifer M, Berg S, Reynolds AB . A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 1994; 76: 789–791.

    CAS  PubMed  Google Scholar 

  140. Reynolds AB, Herbert L, Cleveland JL, Berg ST, Gaut JR . p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. Oncogene 1992; 7: 2439–2445.

    CAS  PubMed  Google Scholar 

  141. Thoreson MA, Anastasiadis PZ, Daniel JM, Ireton RC, Wheelock MJ, Johnson KR et al. Selective uncoupling of p120(ctn) from E-cadherin disrupts strong adhesion. J Cell Biol 2000; 148: 189–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Reynolds AB, Daniel J, McCrea PD, Wheelock MJ, Wu J, Zhang Z . Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol 1994; 14: 8333–8342.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Dillon DA, D'Aquila T, Reynolds AB, Fearon ER, Rimm DL . The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and E-cadherin. Am J Pathol 1998; 152: 75–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Anastasiadis PZ, Moon SY, Thoreson MA, Mariner DJ, Crawford HC, Zheng Y et al. Inhibition of RhoA by p120 catenin. Nat Cell Biol 2000; 2: 637–644.

    CAS  PubMed  Google Scholar 

  145. Anastasiadis PZ, Reynolds AB . Regulation of Rho GTPases by p120-catenin. Curr Opin Cell Biol 2001; 13: 604–610.

    CAS  PubMed  Google Scholar 

  146. Birukova AA, Zebda N, Cokic I, Fu P, Wu T, Dubrovskyi O et al. p190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury. Exp Cell Res 2011; 317: 859–872.

    CAS  PubMed  Google Scholar 

  147. Ponik SM, Trier SM, Wozniak MA, Eliceiri KW, Keely PJ . RhoA is down-regulated at cell-cell contacts via p190RhoGAP-B in response to tensional homeostasis. Mol Biol Cell 2013; 24: 1688–1699.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Wildenberg GA, Dohn MR, Carnahan RH, Davis MA, Lobdell NA, Settleman J et al. p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 2006; 127: 1027–1039.

    CAS  PubMed  Google Scholar 

  149. Smith AL, Dohn MR, Brown MV, Reynolds AB . Association of Rho-associated protein kinase 1 with E-cadherin complexes is mediated by p120-catenin. Mol Biol Cell 2012; 23: 99–9110.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Miyashita Y, Ozawa M . Increased internalization of p120-uncoupled E-cadherin and a requirement for a dileucine motif in the cytoplasmic domain for endocytosis of the protein. J Biol Chem 2007; 282: 11540–11548.

    CAS  PubMed  Google Scholar 

  151. Sato K, Watanabe T, Wang S, Kakeno M, Matsuzawa K, Matsui T et al. Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell 2011; 22: 3103–3119.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Kanner SB, Reynolds AB, Parsons JT . Tyrosine phosphorylation of a 120-kilodalton pp60src substrate upon epidermal growth factor and platelet-derived growth factor receptor stimulation and in polyomavirus middle-T-antigen-transformed cells. Mol Cell Biol 1991; 11: 713–720.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Downing JR, Reynolds AB . PDGF, CSF-1, and EGF induce tyrosine phosphorylation of p120, a pp60src transformation-associated substrate. Oncogene 1991; 6: 607–613.

    CAS  PubMed  Google Scholar 

  154. Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ . E-cadherin’s dark side: possible role in tumor progression. Biochim Biophys Acta 2012; 1826: 23–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Smalley-Freed WG, Efimov A, Burnett PE, Short SP, Davis MA, Gumucio DL et al. p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice. J Clin Invest 2010; 120: 1824–1835.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Smalley-Freed WG, Efimov A, Short SP, Jia P, Zhao Z, Washington MK et al. Adenoma formation following limited ablation of p120-catenin in the mouse intestine. PLoS One 2011; 6: e19880.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Perez-Moreno M, Davis MA, Wong E, Pasolli HA, Reynolds AB, Fuchs E . p120-catenin mediates inflammatory responses in the skin. Cell 2006; 124: 631–644.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Stairs DB, Bayne LJ, Rhoades B, Vega ME, Waldron TJ, Kalabis J et al. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Cancer Cell 2011; 19: 470–483.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Kurley SJ, Bierie B, Carnahan RH, Lobdell NA, Davis MA, Hofmann I et al. p120-catenin is essential for terminal end bud function and mammary morphogenesis. Development 2012; 139: 1754–1764.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Davis MA, Reynolds AB . Blocked acinar development, E-cadherin reduction, and intraepithelial neoplasia upon ablation of p120-catenin in the mouse salivary gland. Dev Cell 2006; 10: 21–31.

    CAS  PubMed  Google Scholar 

  161. Thoreson MA, Reynolds AB . Altered expression of the catenin p120 in human cancer: implications for tumor progression. Differentiation 2002; 70: 583–589.

    CAS  PubMed  Google Scholar 

  162. David E, Tramontin T, Zemmel R . Pharmaceutical R&D: the road to positive returns. Nat Rev Drug Discov 2009; 8: 609–610.

    CAS  PubMed  Google Scholar 

  163. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov 2010; 9: 203–214.

    CAS  PubMed  Google Scholar 

  164. Berggren R, Moller M, Moss R, Poda P, Smietana K . Outlook for the next 5 years in drug innovation. Nat Rev Drug Discov 2012; 11: 435–436.

    CAS  PubMed  Google Scholar 

  165. Brunton VG, Frame MC . Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol 2008; 8: 427–432.

    CAS  PubMed  Google Scholar 

  166. Creedon H, Brunton VG . Src kinase inhibitors: promising cancer therapeutics? Crit Rev Oncog 2012; 17: 145–159.

    PubMed  Google Scholar 

  167. Abbott BL . Dasatinib: from treatment of imatinib-resistant or -intolerant patients with chronic myeloid leukemia to treatment of patients with newly diagnosed chronic phase chronic myeloid leukemia. Clin Ther 2012; 34: 272–281.

    CAS  PubMed  Google Scholar 

  168. Quintas-Cardama A, Kantarjian H, Cortes J . Bosutinib for the treatment of chronic myeloid leukemia in chronic phase. Drugs Today 2012; 48: 177–188.

    CAS  Google Scholar 

  169. Hantschel O, Grebien F, Superti-Furga G . The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL. Cancer Res 2012; 72: 4890–4895.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 2010; 1804: 445–453.

    CAS  PubMed  Google Scholar 

  171. Parsons SJ, Parsons JT . Src family kinases, key regulators of signal transduction. Oncogene 2004; 23: 7906–7909.

    CAS  PubMed  Google Scholar 

  172. Frame MC . Newest findings on the oldest oncogene; how activated src does it. J Cell Sci 2004; 117 (Pt 7): 989–998.

    CAS  PubMed  Google Scholar 

  173. Gallick GE, Corn PG, Zurita AJ, Lin SH . Small-molecule protein tyrosine kinase inhibitors for the treatment of metastatic prostate cancer. Future Med Chem 2012; 4: 107–119.

    CAS  PubMed  Google Scholar 

  174. Kopetz S, Shah AN, Gallick GE . Src continues aging: current and future clinical directions. Clin Cancer Res 2007; 13: 7232–7236.

    CAS  PubMed  Google Scholar 

  175. Tilghman RW, Parsons JT . Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol 2008; 18: 45–52.

    CAS  PubMed  Google Scholar 

  176. Tomar A, Schlaepfer DD . Focal adhesion kinase: switching between GAPs and GEFs in the regulation of cell motility. Curr Opin Cell Biol 2009; 21: 676–683.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Schaller MD . Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 2010; 123 (Pt 7): 1007–1013.

    CAS  PubMed  Google Scholar 

  178. Zhao X, Guan J-L . Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev 2011; 63: 610–615.

    CAS  PubMed  Google Scholar 

  179. Han EK-H, McGonigal T . Role of focal adhesion kinase in human cancer: a potential target for drug discovery. Anticancer Agents Med Chem 2007; 7: 681–684.

    CAS  PubMed  Google Scholar 

  180. Schwock J, Dhani N, Hedley DW . Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin Ther Targets 2010; 14: 77–94.

    CAS  PubMed  Google Scholar 

  181. Ma WW . Development of focal adhesion kinase inhibitors in cancer therapy. Anticancer Agents Med Chem 2011; 11: 638–642.

    CAS  PubMed  Google Scholar 

  182. Schultze A, Fiedler W . Clinical importance and potential use of small molecule inhibitors of focal adhesion kinase. Anticancer Agents Med Chem 2011; 11: 593–599.

    CAS  PubMed  Google Scholar 

  183. Dunn KB, Heffler M, Golubovskaya VM . Evolving therapies and FAK inhibitors for the treatment of cancer. Anticancer Agents Med Chem 2010; 10: 722–734.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Reynolds AB, Roczniak-Ferguson A . Emerging roles for p120-catenin in cell adhesion and cancer. Oncogene 2004; 23: 7947–7956.

    CAS  PubMed  Google Scholar 

  185. Reynolds AB . p120-catenin: past and present. Biochim Biophys Acta. 2007; 1773: 2–7.

    CAS  PubMed  Google Scholar 

  186. Ammer AG, Weed SA . Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motil Cytoskeleton 2008; 65: 687–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kirkbride KC, Sung BH, Sinha S, Weaver AM . Cortactin: a multifunctional regulator of cellular invasiveness. Cell Adh Migr 2011; 5: 187–198.

    PubMed  PubMed Central  Google Scholar 

  188. Wells JA, McClendon CL . Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 2007; 450: 1001–1009.

    CAS  PubMed  Google Scholar 

  189. Khan SH, Ahmad F, Ahmad N, Flynn DC, Kumar R . Protein-protein interactions: principles, techniques, and their potential role in new drug development. J Biomol Struct Dyn 2011; 28: 929–938.

    CAS  PubMed  Google Scholar 

  190. Radi M, Schenone S, Botta M . Allosteric inhibitors of Bcr-Abl: towards novel myristate-pocket binders. Curr Pharm Biotechnol (e-pub ahead of print 20 March 2012).

  191. Hopkins AL . Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008; 4: 682–690.

    CAS  PubMed  Google Scholar 

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Acknowledgements

Many thanks to Steven Bernhardt for critical review and suggestions for organization of this review. Also, we are grateful for the help of Jenny Michelle Reed in the preparation of this review.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA

    A B Reynolds

  2. Arrowhead Research Corporation, Madison, WI, USA

    S B Kanner

  3. Departments of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA

    A H Bouton

  4. Department of Biochemistry, 3124 HSN, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA

    M D Schaller

  5. Department of Neurobiology and Anatomy, 1833 Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV, USA

    S A Weed

  6. Department of Medical Lab Sciences, College of Health Sciences, University of Delaware, Newark, DE, USA

    D C Flynn

  7. Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Cancer Center, Charlottesville, VA, USA

    J T Parsons

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  1. A B Reynolds
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  2. S B Kanner
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Correspondence to D C Flynn.

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Reynolds, A., Kanner, S., Bouton, A. et al. SRChing for the substrates of Src. Oncogene 33, 4537–4547 (2014). https://doi.org/10.1038/onc.2013.416

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