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  • Review Article
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A renaissance for SRC

Key Points

  • v-src was the first of numerous viral oncogenes to be identified and is among the best studied of these. The cellular counterpart of this oncogene — c-SRC — is implicated in a range of human cancers.

  • Both overexpression and overactivation of c-SRC can promote the development of cancer. The structural mechanisms by which c-SRC kinase activity is regulated are now well established, and c-SRC is known to have a negative-regulatory domain that is itself regulated through phosphorylation.

  • c-SRC kinase activity is regulated by several mechanisms, including activation by receptor tyrosine kinases and cytoplasmic phosphatases. Levels of c-SRC protein can also be regulated, for example, by targeting this protein for degradation in the ubiquitin–proteasome pathway. In addition, c-SRC function can also be modulated by regulation of its cellular localization.

  • A wide range of c-SRC substrates have been identified, which has led to a better understanding of c-SRC-mediated signal transduction. These substrates include focal-adhesion proteins, adaptor proteins and transcription factors.

  • In addition to cell proliferation, SRC proteins regulate three main cellular functions that ultimately control the behaviour of transformed cells: adhesion, invasion and motility. These functions might also contribute to tumour progression and metastasis.

  • Recently, drug-discovery efforts have led to the development of several c-SRC inhibitors for potential use as anticancer therapeutics.

Abstract

The c-SRC non-receptor tyrosine kinase is overexpressed and activated in a large number of human malignancies and has been linked to the development of cancer and progression to distant metastases. These observations have led to the recent targeting of c-SRC for the development of anticancer therapeutics, which show promise as a new avenue for cancer treatment. Despite this, however, the precise functions of c-SRC in cancer remain unclear. In addition to increasing cell proliferation, a key role of c-SRC in cancer seems to be to promote invasion and motility, functions that might contribute to tumour progression.

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Figure 1: Structure and activation of SRC proteins.
Figure 2: Regulation of c-SRC.
Figure 3: Transformation of fibroblasts by v-src.
Figure 4: Levels of c-SRC expression and activity in colorectal cancer progression.
Figure 5: Cell adhesion at adherens junctions and focal adhesions.
Figure 6: Effects of c-SRC on tumour-cell behaviour.

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References

  1. Martin, G. S. The hunting of the Src. Nature Rev. Mol. Cell Biol. 2, 467–475 (2001).

    Article  CAS  Google Scholar 

  2. Rous, P. A. Transmission of a malignant new growth by means of a cell-free filtrate. JAMA 56, 198 (1911).

    Google Scholar 

  3. Rous, P. A. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 13, 397–411 (1911). References 2 and 3 are seminal papers describing the studies that first identified a transmissible agent capable of cellular transformation. This was later found to be v- Src , the first oncogene to be identified.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rubin, H. Quantitative relations between causative virus and cell in the Rous No. 1 chicken sarcoma. Virology 6, 669–688 (1955).

    Google Scholar 

  5. Martin, G. S. Rous sarcoma virus: a function required for the maintenance of the transformed state. Nature 227, 1021–1023 (1970).

    Article  CAS  PubMed  Google Scholar 

  6. Czernilofsky, A. P. et al. Corrections to the nucleotide sequence of the src gene of Rous sarcoma virus. Nature 301, 736–738 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. Czernilofsky, A. P. et al. Nucleotide sequence of an avian sarcoma virus oncogene (src) and proposed amino acid sequence for gene product. Nature 287, 198–203 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. Takeya, T. & Hanafusa, H. DNA sequence of the viral and cellular src gene of chickens. II. Comparison of the src genes of two strains of avian sarcoma virus and of the cellular homolog. J. Virol. 44, 12–18 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Takeya, T., Feldman, R. A. & Hanafusa, H. DNA sequence of the viral and cellular src gene of chickens. 1. Complete nucleotide sequence of an EcoRI fragment of recovered avian sarcoma virus which codes for gp37 and pp60src. J. Virol. 44, 1–11 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Varmus, H. E., Quintrell, N. & Wyke, J. Revertants of an ASV-transformed rat cell line have lost the complete provius or sustained mutations in src. Virology 108, 28–46 (1981).

    Article  CAS  PubMed  Google Scholar 

  11. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Huebner, R. J. & Todaro, G. J. Oncogenes of RNA tumor viruses as determinants of cancer. Proc. Natl Acad. Sci. USA 64, 1087–1094 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).

    Article  CAS  PubMed  Google Scholar 

  14. Levinson, A. D., Oppermann, H., Levintow, L., Varmus, H. E. & Bishop, J. M. Evidence that the transforming gene of avian sarcoma virus encodes a protein kinase associated with a phosphoprotein. Cell 15, 561–572 (1978).

    Article  CAS  PubMed  Google Scholar 

  15. Collett, M. S. & Erikson, R. L. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc. Natl Acad. Sci. USA 75, 2021–2024 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hunter, T. & Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Parsons, J. T. & Weber, M. J. Genetics of src: structure and functional organization of a protein tyrosine kinase. Curr. Top. Microbiol. Immunol. 147, 79–127 (1989).

    CAS  PubMed  Google Scholar 

  18. Jove, R. & Hanafusa, H. Cell transformation by the viral src oncogene. Annu. Rev. Cell Biol. 3, 31–56 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Roche, S., Fumagalli, S. & Courtneidge, S. A. Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Science 269, 1567–1569 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Jones, R. J. et al. Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br. J. Cancer 87, 1128–1135 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brunton, V. G., Ozanne, B. W., Paraskeva, C. & Frame, M. C. A role for epidermal growth factor receptor, c-Src and focal adhesion kinase in an in vitro model for the progression of colon cancer. Oncogene 14, 283–293 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Frame, M. C. Src in cancer: deregulation and consequences for cell behaviour. Biochim. Biophys. Acta 1602, 114–130 (2002).

    CAS  PubMed  Google Scholar 

  23. Irby, R. B. & Yeatman, T. J. Role of Src expression and activation in human cancer. Oncogene 19, 5636–5642 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Talamonti, M. S., Roh, M. S., Curley, S. A. & Gallick, G. E. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J. Clin. Invest. 91, 53–60 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Weber, T. K., Steele, G. & Summerhayes, I. C. Differential pp60c-src activity in well and poorly differentiated human colon carcinomas and cell lines. J. Clin. Invest. 90, 815–821 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maa, M. C., Leu, T. H., McCarley, D. J., Schatzman, R. C. & Parsons, S. J. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc. Natl Acad. Sci. USA 92, 6981–6985 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mao, W. et al. Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential. Oncogene 15, 3083–3090 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Hynes, N. E. Tyrosine kinase signalling in breast cancer. Breast Cancer Res. 2, 154–157 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wiener, J. R. et al. Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecol. Oncol. 88, 73–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Masaki, T. et al. pp60c-src activation in hepatocellular carcinoma of humans and LEC rats. Hepatology 27, 1257–1264 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Masaki, T. et al. Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma. Hepatology 29, 379–384 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Cam, W. R. et al. Reduced C-terminal Src kinase activity is correlated inversely with pp60(c-src) activity in colorectal carcinoma. Cancer 92, 61–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Brown, M. T. & Cooper, J. A. Regulation, substrates and functions of src. Biochim. Biophys. Acta 1287, 121–149 (1996).

    PubMed  Google Scholar 

  34. Mori, S. et al. Identification of two juxtamembrane autophosphorylation sites in the PDGFβ-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J. 12, 2257–2264 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yamaguchi, H. & Hendrickson, W. A. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 384, 484–489 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Irby, R. B. et al. Activating SRC mutation in a subset of advanced human colon cancers. Nature Genet. 21, 187–190 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Cooper, J. A., Gould, K. L., Cartwright, C. A. & Hunter, T. Tyr527 is phosphorylated in pp60c-src: implications for regulation. Science 231, 1431–1434 (1986).

    Article  CAS  PubMed  Google Scholar 

  38. Zheng, X. M., Wang, Y. & Pallen, C. J. Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature 359, 336–339 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Jung, E. J. & Kim, C. W. Interaction between chicken protein tyrosine phosphatase 1 (CPTP1)-like rat protein phosphatase 1 (PTP1) and p60(v-src) in v-src-transformed Rat-1 fibroblasts. Exp. Mol. Med. 34, 476–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Bjorge, J. D., Pang, A. & Fujita, D. J. Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J. Biol. Chem. 275, 41439–41446 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Schaller, M. D. et al. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol. Cell. Biol. 14, 1680–1688 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Burnham, M. R. et al. Regulation of c-SRC activity and function by the adapter protein CAS. Mol. Cell. Biol. 20, 5865–5878 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Thomas, J. W. et al. SH2- and SH3-mediated interactions between focal adhesion kinase and Src. J. Biol. Chem. 273, 577–583 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Tice, D. A., Biscardi, J. S., Nickles, A. L. & Parsons, S. J. Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc. Natl Acad. Sci. USA 96, 1415–1420 (1999). This paper was one of the first to demonstrate synergism between c-SRC and receptor tyrosine kinases resulting in cellular transformation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Muthuswamy, S. K., Siegel, P. M., Dankort, D. L., Webster, M. A. & Muller, W. J. Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. Mol. Cell. Biol. 14, 735–743 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. DeMali, K. A., Godwin, S. L., Soltoff, S. P. & Kazlauskas, A. Multiple roles for Src in a PDGF-stimulated cell. Exp. Cell Res. 253, 271–279 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Bowman, T. et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl Acad. Sci. USA 98, 7319–7324 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Landgren, E., Blume-Jensen, P., Courtneidge, S. A. & Claesson-Welsh, L. Fibroblast growth factor receptor-1 regulation of Src family kinases. Oncogene 10, 2027–2035 (1995).

    CAS  PubMed  Google Scholar 

  49. Courtneidge, S. A. et al. Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor. EMBO J. 12, 943–950 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim, M., Tezuka, T., Tanaka, K. & Yamamoto, T. Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 23, 1645–1655 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Kamei, T. et al. C-Cbl protein in human cancer tissues is frequently tyrosine phosphorylated in a tumor-specific manner. Int. J. Oncol. 17, 335–339 (2000).

    CAS  PubMed  Google Scholar 

  52. Akhand, A. A. et al. Nitric oxide controls src kinase activity through a sulfhydryl group modification-mediated Tyr-527-independent and Tyr-416-linked mechanism. J. Biol. Chem. 274, 25821–25826 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Sugimura, M. et al. Mutation of the SRC gene in endometrial carcinoma. Jpn J. Cancer Res. 91, 395–398 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Laghi, L. et al. Lack of mutation at codon 531 of SRC in advanced colorectal cancers from Italian patients. Br. J. Cancer 84, 196–198 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nilbert, M. & Fernebro, E. Lack of activating c-SRC mutations at codon 531 in rectal cancer. Cancer Genet. Cytogenet. 121, 94–95 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, N. M., Yeh, K. T., Tsai, C. H., Chen, S. J. & Chang, J. G. No evidence of correlation between mutation at codon 531 of src and the risk of colon cancer in Chinese. Cancer Lett. 150, 201–204 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Daigo, Y. et al. Absence of genetic alteration at codon 531 of the human c-src gene in 479 advanced colorectal cancers from Japanese and Caucasian patients. Cancer Res. 59, 4222–4224 (1999).

    CAS  PubMed  Google Scholar 

  58. Nigg, E. A., Sefton, B. M., Hunter, T., Walter, G. & Singer, S. J. Immunofluorescent localization of the transforming protein of Rous sarcoma virus with antibodies against a synthetic src peptide. Proc. Natl Acad. Sci. USA 79, 5322–5326 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Johnson, L. N., Noble, M. E. & Owen, D. J. Active and inactive protein kinases: structural basis for regulation. Cell 85, 149–158 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Sefton, B. M., Trowbridge, I. S., Cooper, J. A. & Scolnick, E. M. The transforming proteins of Rous sarcoma virus, Harvey sarcoma virus and Abelson virus contain tightly bound lipid. Cell 31, 465–474 (1982).

    Article  CAS  PubMed  Google Scholar 

  61. Timpson, P., Jones, G. E., Frame, M. C. & Brunton, V. G. Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity. Curr. Biol. 11, 1836–1846 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Courtneidge, S. A. Isolation of novel Src substrates. Biochem. Soc. Trans. 31, 25–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Staley, C. A., Parikh, N. U. & Gallick, G. E. Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src. Cell Growth Differ. 8, 269–274 (1997).

    CAS  PubMed  Google Scholar 

  64. Ramdas, L. et al. A tyrphostin-derived inhibitor of protein tyrosine kinases: isolation and characterization. Arch. Biochem. Biophys. 323, 237–242 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Iravani, S. et al. Elevated c-Src protein expression is an early event in colonic neoplasia. Lab. Invest. 78, 365–371 (1998).

    CAS  PubMed  Google Scholar 

  66. Termuhlen, P. M., Curley, S. A., Talamonti, M. S., Saboorian, M. H. & Gallick, G. E. Site-specific differences in pp60c-src activity in human colorectal metastases. J. Surg. Res. 54, 293–298 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Summy, J. M. & Gallick, G. E. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 22, 337–358 (2003). This review discusses the role of c- SRC in promoting the spread of cancer.

    Article  CAS  PubMed  Google Scholar 

  68. Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Carragher, N. O., Westhoff, M. A., Fincham, V. J., Schaller, M. D. & Frame, M. C. A novel role for FAK as a protease-targeting adaptor protein: regulation by p42 ERK and Src. Curr. Biol. 13, 1442–1450 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Carragher, N. O. & Frame, M. C. Calpain: a role in cell transformation and migration. Int. J. Biochem. Cell Biol. 34, 1539–1543 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Sastry, S. K. & Burridge, K. Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp. Cell Res. 261, 25–36 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Jamora, C. & Fuchs, E. Intercellular adhesion, signalling and the cytoskeleton. Nature Cell Biol. 4, E101–E108 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Zamir, E. & Geiger, B. Molecular complexity and dynamics of cell-matrix adhesions. J. Cell Sci. 114, 3583–3590 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Fujisawa, K. et al. Different regions of Rho determine Rho-selective binding of different classes of Rho target molecules. J. Biol. Chem. 273, 18943–18949 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Hynes, R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69, 11–25 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Yap, A. S., Brieher, W. M. & Gumbiner, B. M. Molecular and functional analysis of cadherin-based adherens junctions. Annu. Rev. Cell Dev. Biol. 13, 119–146 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Chen, Y. T., Stewart, D. B. & Nelson, W. J. Coupling assembly of the E-cadherin/β-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells. J. Cell Biol. 144, 687–699 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Aberle, H. et al. Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J. Cell Sci. 107 (Pt 12), 3655–3663 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 100, 209–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Reynolds, A. B. et al. Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol. Cell. Biol. 14, 8333–8342 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Chang, J. H., Gill, S., Settleman, J. & Parsons, S. J. c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation. J. Cell Biol. 130, 355–368 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Fincham, V. J. & Frame, M. C. The catalytic activity of Src is dispensable for translocation to focal adhesions but controls the turnover of these structures during cell motility. EMBO J. 17, 81–92 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Avizienyte, E. et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nature Cell Biol. 4, 632–638 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Zou, J. X., Liu, Y., Pasquale, E. B. & Ruoslahti, E. Activated SRC oncogene phosphorylates R-ras and suppresses integrin activity. J. Biol. Chem. 277, 1824–1827 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Fujita, Y. et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature Cell Biol. 4, 222–231 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  87. Laukaitis, C. M., Webb, D. J., Donais, K. & Horwitz, A. F. Differential dynamics of α5 integrin, paxillin, and α-actinin during formation and disassembly of adhesions in migrating cells. J. Cell Biol. 153, 1427–1440 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Burridge, K. & Chrzanowska-Wodnicka, M. Focal adhesions, contractility, and signaling. Annu. Rev. Cell Dev. Biol. 12, 463–518 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Frixen, U. H. et al. E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol. 113, 173–185 (1991).

    Article  CAS  PubMed  Google Scholar 

  90. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Noritake, H., Miyamori, H., Goto, C., Seiki, M. & Sato, H. Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in metastatic MDCK cells transformed by v-src. Clin. Exp. Metastasis 17, 105–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Hsia, D. A. et al. Differential regulation of cell motility and invasion by FAK. J. Cell Biol. 160, 753–767 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schaller, M. D. Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim. Biophys. Acta. 1540, 1–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Hauck, C. R., Hsia, D. A. & Schlaepfer, D. D. The focal adhesion kinase: a regulator of cell migration and invasion. IUBMB Life 53, 115–119 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Owens, L. V. et al. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res. 55, 2752–2755 (1995).

    CAS  PubMed  Google Scholar 

  96. Kornberg, L. J. Focal adhesion kinase and its potential involvement in tumor invasion and metastasis. Head Neck 20, 745–752 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Moissoglu, K. & Gelman, I. H. v-Src rescues actin-based cytoskeletal architecture and cell motility and induces enhanced anchorage independence during oncogenic transformation of focal adhesion kinase-null fibroblasts. J. Biol. Chem. 278, 47946–47959 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Ilic, D. et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. Webb, D. J. et al. FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nature Cell Biol. 6, 154–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Schaller, M. D. & Parsons, J. T. pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol. Cell. Biol. 15, 2635–2645 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Irby, R. et al. Overexpression of normal c-Src in poorly metastatic human colon cancer cells enhances primary tumor growth but not metastatic potential. Cell Growth Differ. 8, 1287–1295 (1997).

    CAS  PubMed  Google Scholar 

  102. Boyer, B., Bourgeois, Y. & Poupon, M. F. Src kinase contributes to the metastatic spread of carcinoma cells. Oncogene 21, 2347–2356 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Nakagawa, T. et al. Overexpression of the csk gene suppresses tumor metastasis in vivo. Int. J. Cancer. 88, 384–391 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83 (1995). Describes the identification of STAT3 as a downstream signal-transduction target of SRC.

    Article  CAS  PubMed  Google Scholar 

  105. Niu, G. et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Yu, H. & Jove, R. The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    Article  CAS  Google Scholar 

  107. Kilarski, W. W., Jura, N. & Gerwins, P. Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for a mechanism involving organization of the actin cytoskeleton. Exp. Cell Res. 291, 70–82 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Laird, A. D. et al. Src family kinase activity is required for signal tranducer and activator of transcription 3 and focal adhesion kinase phosphorylation and vascular endothelial growth factor signaling in vivo and for anchorage-dependent and-independent growth of human tumor cells. Mol. Cancer Ther. 2, 461–469 (2003).

    CAS  PubMed  Google Scholar 

  109. Blake, R. A. et al. SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol. Cell. Biol. 20, 9018–9027 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Golas, J. M. et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 63, 375–381 (2003).

    CAS  PubMed  Google Scholar 

  111. Shakespeare, W. C. et al. Novel bone-targeted Src tyrosine kinase inhibitor drug discovery. Curr. Opin. Drug Discov. Devel. 6, 729–741 (2003).

    CAS  PubMed  Google Scholar 

  112. Golubovskaya, V. M. et al. Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment and apoptosis in colon cancer cell lines. Mol. Cancer Res. 1, 755–764 (2003).

    CAS  PubMed  Google Scholar 

  113. Malek, R. L. et al. Identification of Src transformation fingerprint in human colon cancer. Oncogene 21, 7256–7265 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author thanks R. Jove for his critical comments.

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DATABASES

Cancer.gov

breast cancer

colon cancer

endometrial cancer

gastric cancer

hepatocellular cancer

lung cancer

oesophageal cancer

ovarian cancer

pancreatic cancer

Entrez Gene

BLK

CAS

CHK

CSK

c-SRC

E-cadherin

EGFR

FAK

FGR

FYN

HCK

LCK

LYN

PTP1B

PTPα

RHOA

RRAS

SHP1

SHP2

YES

FURTHER INFORMATION

Publication list of the Program for Genomic Application

Glossary

SH DOMAINS

SRC homology domains are distinct regions of amino-acid homology that possess well-defined biochemical functions.

MYRISTOYLATION

Refers to the accession of fatty moieties that allow association with the inner layer of the plasma membrane.

LAMELLIPODIA

Thin, sheet-like cell extensions of cytoplasm found at the leading edge of crawling cells. They form transient adhesions with the cell substrate, enabling the cell to move along a surface.

FILOPODIA

Small membrane projections, rich in actin, which emanate from the leading edge of the cell in the direction of movement.

G PROTEINS

GTP-binding intracellular-membrane-associated proteins that are activated by receptor stimulation.

DENSITY INHIBITION

The process by which non-transformed cells limit their proliferation when a certain density is reached due to physical contact with other cells or colonies.

CADHERINS

A group of functionally related glycoproteins that are involved in calcium-dependent cell-to-cell adhesion.

SELECTINS

A family of cell-adhesion molecules consisting of a lectin-like domain, an epidermal growth-factor-like domain, and a variable number of domains that are homologous to complement-binding proteins. Selectins mediate the binding of leukocytes to the vascular endothelium.

METALLOPROTEINASES

A group of enzymes that can break down extracellular matrix proteins and require zinc or calcium atoms for catalytic activity. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumour-cell metastasis.

TIMPs

Tissue inhibitors of metalloproteinases are a family of secreted proteins that have a crucial role in regulating the activity of metalloproteinases. They influence the activation of the pro-metalloproteinase and act to modulate proteolysis of the extracellular matrix, notably during tissue remodelling and inflammatory processes.

INVADOPODIA

Invadopodia are specialized plasma-membrane structures associated with invading cells and extracellular-matrix degradation. These cellular protrusions are enriched in integrins and their associated tyrosine-kinase signalling molecules, metalloproteinases, and actin and actin-associated proteins.

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Yeatman, T. A renaissance for SRC. Nat Rev Cancer 4, 470–480 (2004). https://doi.org/10.1038/nrc1366

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