Src as a Target for Pharmaceutical Intervention

Potential and Limitations
  • Mira Šuša
  • Martin Missbach
  • Rainer Gamse
  • Michaela Kneissel
  • Thomas Buhl
  • Jürg A. Gasser
  • Markus Glatt
  • Terence O’Reilly
  • Anna Teti
  • Jonathan Green
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Src is a nonreceptor type protein tyrosine kinase and a prototype of a family consisting of eight members in vertebrates: Src, Yes, Fyn, Fgr, Lyn, Hck, Lck, Blk. Src is an evolutionary well-conserved gene in vertebrates with homologs expressed in invertebrates. When compared with other nonreceptor type 1 tyrosine kinases in the human genome, the Src family is the largest, with its members very closely related to each other, particularly those within two Src family subgroups (Fig. 1). Such a high degree of similarity is also present in receptor tyrosine kinase families, e.g., the epidermal growth factor receptor (EGFR) family, which is the most similar to nonreceptor tyrosine kinases (Fig. 1). Interestingly, the presence of many close family members within the Src family corresponds to their biological activity, which is linked to physical and functional association with receptor tyrosine kinases at the plasma membrane (1).

Keywords

Tyrosine Leukemia Anemia Integrin Gelatin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Neet K, Hunter T. Vertebrate non-receptor protein tyrosine kinase families. Genes Cells 1996; 1:147–169.PubMedCrossRefGoogle Scholar
  2. 2.
    Brown MT, Cooper JA. Regulation, substrates and functions of src. Biochim Biophys Acta 1996; 1287:121–149.PubMedGoogle Scholar
  3. 3.
    Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 1997; 13:513–609.PubMedCrossRefGoogle Scholar
  4. 4.
    Guy CT, Muthuswamy SK, Cardiff RD, Soriano P, Muller WJ. Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev 1994; 8:23–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Biscardi JS, Tice DA, Parsons SJ. c-Src, receptor tyrosine kinases, and human cancer. Adv Cancer Res 1999; 76:61–119.PubMedGoogle Scholar
  6. 6.
    Kloth MT, Laughlin KK, Biscardi JS, Boerner JL, Parsons SJ, Silva CM. STAT5b, a mediator of synergism between c-Src and the epidermal growth factor receptor. J Biol Chem 2003; 278:1671–1679.PubMedCrossRefGoogle Scholar
  7. 7.
    Li Y, Tondravi M, Liu J, et al. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res 2001; 61:6906–6911.PubMedGoogle Scholar
  8. 8.
    Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE. Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 2002; 94:344–351.PubMedCrossRefGoogle Scholar
  9. 9.
    Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991; 64:693–702.PubMedCrossRefGoogle Scholar
  10. 10.
    Duong LK, Lakkakorpi PT, Nakamura I, Machwate M, Nagy RM, Rodan GA. PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. J Clin Invest 1998; 102:881–892.PubMedCrossRefGoogle Scholar
  11. 11.
    Jeschke M, Brandi ML, Susa M. Expression of Src family kinases and their putative substrates in the human precosteoclastic cell line FLG 29.1. J Bone Miner Res 1998; 13:1880–1889.PubMedCrossRefGoogle Scholar
  12. 12.
    Susa M, Missbach M, Green J. Src inhibitors: drugs for the treatment of osteoporosis, cancer or both? Trends Pharmacol Sci 2000; 21:489–495.CrossRefGoogle Scholar
  13. 13.
    Susa M, Teti A. Tyrosine kinase Src inhibitors: potential therapeutic applications. Drug News Perspect 2000; 13:169–175.PubMedCrossRefGoogle Scholar
  14. 14.
    Altmann E, Widler L, Missbach M. N(7)-substituted-5-aryl-pyrrolo[2,3-d]pyrimidines represent a versatile class of potent inhibitors of the tyrosine kinase c-Src. Med Chem 2002; 2:201–208.Google Scholar
  15. 15.
    Metcalf CA III, van Schrevendijk MR, Dalgarno DC, Sawyer TK. Targeting protein kinases for bone disease: discovery and development of Src inhibitors. Curr Pharm Des 2002; 8:2049–2075.PubMedCrossRefGoogle Scholar
  16. 16.
    Blake RA, Broome MA, Liu X, et al. SU6656, a selective Src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol 2000; 20:9018–9027.PubMedCrossRefGoogle Scholar
  17. 17.
    Shakespeare WC. Src tyrosine kinase inhibitors for bone diseases. Abstracts of Papers, 223rd American Chemical Society National Meeting, April 7–11 2002, Orlando.Google Scholar
  18. 18.
    Missbach M, Jeschke J, Feyen J, et al. A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resportion in vitro and in rodent models in vivo. Bone 1999; 24:437–449.PubMedCrossRefGoogle Scholar
  19. 19.
    Recchia I, Rucci N, Funari A, et al. Reduction of c-Src activity by substituted 5,7-diphenylpyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK 1/2 pathway. Bone 2004; 34:65–79.PubMedCrossRefGoogle Scholar
  20. 20.
    Tang D, Wu D, Hirao A, et al. ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem 2002; 277:12710–12717.PubMedCrossRefGoogle Scholar
  21. 21.
    Recchia I, Rucci N, Festuccia C, et al. Pyrrolopyrimidine c-Src inhibitors reduce prostate cancer cell activity in vitro. Eur J Cancer 2003; 39:1927–1935.PubMedCrossRefGoogle Scholar
  22. 22.
    Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 1999; 4:915–924.PubMedCrossRefGoogle Scholar
  23. 23.
    He H, Hirokawa Y, Manser E, Lim L, Levitzki A, Maruta H. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Cancer J 2001; 7:191–202.PubMedGoogle Scholar
  24. 24.
    Susa M, Luong-Nguyen N-H, Crespo J, Maier R, Missbach M, McMaster G. Active recombinant human tyrosine kinase c-Yes: expression in baculovirus system, purification, comparison to c-Src, and inhibition by a c-Src inhibitor. Protein Expr Purif 2000; 19:99–106.PubMedCrossRefGoogle Scholar
  25. 25.
    Menke A, Philippi C, Vogelmann R, et al. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res 2001; 61:3508–3517.PubMedGoogle Scholar
  26. 26.
    Su W, Sin M, Darrow A, Sherman L. Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberant CD44 expression. Glia 2003; 42:350–358.PubMedCrossRefGoogle Scholar
  27. 27.
    Donato NJ, Wu JY, Stapley J, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101:690–698.PubMedCrossRefGoogle Scholar
  28. 28.
    Warmuth M, Simon N, Mitina O, et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood 2003; 101:664–672.PubMedCrossRefGoogle Scholar
  29. 29.
    Li S, Hu Y. Src kinase inhibitor CGP 76030 synergizes with STI571 in the treatment of B-cell acute lymphoblastic leukemia induced by the BCR/ABL oncogene in mice. The American Society of Hematology, 45th Annual Meeting, December 6–9, 2002, San Diego, California.Google Scholar
  30. 30.
    Golas JM, Arndt K, Etienne C, 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 2003; 63:375–381.PubMedGoogle Scholar
  31. 31.
    Paul R, Zhang ZG, Eliceiri BP, et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med 2001; 7:222–227.PubMedCrossRefGoogle Scholar
  32. 32.
    Fairchild R, Azimzadeh A, Pierson R, Miller G. Activation of Src family members in allografts. American Transplant Congress, April 26–May 1, 2002, Washington, DC.Google Scholar
  33. 33.
    Fowler T, Johansson S, Wary KK, Hook M. Src kinase has a central role in in vitro cellular internalization of Staphylococcus aureus. Cell Microbiol 2003; 5:417–426.PubMedCrossRefGoogle Scholar
  34. 34.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298:1912–1934.PubMedCrossRefGoogle Scholar
  35. 35.
    Gibson TJ, Spring J. Genetic redundancy in vertebrates: polyploidy and persistence of genes encoding multidomain proteins. Trends Genet 1998; 14:46–49.PubMedCrossRefGoogle Scholar
  36. 36.
    Lakkakorpi PT, Nakamura I, Nagy RM, Parsons TJ, Rodan GA, Duong LT. Stable association of PYK2 and p130(Cas) in osteoclasts and their co-localization in the sealing zone. J Biol Chem 1999; 274:4900–4907.PubMedCrossRefGoogle Scholar
  37. 37.
    Olayiole MA, Beuvink I, Horsch K, Daly JM, Hynes NE. ErbB receptor-induced activation of Stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 1999; 274:17209–17218.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Mira Šuša
    • 1
  • Martin Missbach
    • 2
  • Rainer Gamse
    • 3
  • Michaela Kneissel
    • 1
  • Thomas Buhl
    • 1
  • Jürg A. Gasser
    • 1
  • Markus Glatt
    • 1
  • Terence O’Reilly
    • 4
  • Anna Teti
    • 5
  • Jonathan Green
    • 1
  1. 1.Musculoskeletal Diseases (MSD)Novartis Institutes for BioMedical Research Basel, Novartis Pharma AGBaselSwitzerland
  2. 2.Disease Area Bone, Muscle, and Gastrointestinal (BMG)Novartis Institutes for BioMedical Research Basel, Novartis Pharma AGBaselSwitzerland
  3. 3.MSD ManagementNovartis Institutes for BioMedical Research Basel, Novartis Pharma AGBaselSwitzerland
  4. 4.OncologyNovartis Institutes for BioMedical Research Basel, Novartis Pharma AGBaselSwitzerland
  5. 5.University L’AquillaL’AquillaItaly

Personalised recommendations