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c-Kit

c-Kit. Piebaldism Gastrointestinal stromal tumors. c-Kit. A proto-oncogene Encodes a receptor tyrosine kinase type III (similar to PDGFR). Family characteristics: 5 immunoglobulin-like (Ig) domains Cytoplasmic tyrosine kinase domain with large kinase insert.

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c-Kit

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  1. c-Kit Piebaldism Gastrointestinal stromal tumors

  2. c-Kit • A proto-oncogene • Encodes a receptor tyrosine kinase type III (similar to PDGFR) • Family characteristics: • 5 immunoglobulin-like (Ig) domains • Cytoplasmic tyrosine kinase domain with large kinase insert Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30). 31655-31663

  3. Old friend TFG-α Alberts et al. Fig. 15-48

  4. Stem Cell Factor (SCF) • Predominant form is bivalent dimer (Non-covalent interactions) • Important in: • Hematopoietic cell survival, proliferation and differentiation • Mast cell production and function • Melanocyte, germ cell and intestinal pacemaker cell development Zhang, Z. PNAS .2002. 97, 7732-7737

  5. SCF-Kit Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34). 31461-31464

  6. SCF-Kit Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34). 31461-31464

  7. SCF-Kit Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34). 31461-31464

  8. SCF-Kit essential for development of: • Hematopoietic stem cells • Mast cells • Melanocytes • Germ cells • Interstitial cells of Cajal (ICC’s) http://images.google.com/imgres?imgurl=http://

  9. Mouse model • Kit is encoded by the mouse White locus (W) • Mouse mutants: • Null (W -/-): • Pale • Died rapidly of anemia • Constitutive activation • tumorigenic • Heterozygotes (W +/-): • Haploinsufficient • Phenotype varies with gene dosage (e.g. white spotting) • Lack network of ICC and ileum aperistaltic http://www.nature.com/jid/journal/v126/n5/images/5700315i3.jpg

  10. Piebaldism • Autosomal dominant disorder • Occurs due to mutations disrupting expression of proto-oncogene protein c-Kit • Caused by defective proliferation and migration of melanocytes during fetal development • Characterized by white hair patches on the forehead, anterior trunk and extremities. Stolen from Dr. Peifer

  11. Gastrointestinal Stromal Tumors (GISTs) • Mesenchymal tumors (connective tissue) • Believed to arise from interstitial cells of Cajal (autonomic nervous system of the intestine) • ICC’s are Kit/STF positive and dependent • Subset of multipotential stem cell-like cells • Most frequently GISTs occur in older adults (55-60 yrs) • 95% GISTs are caused by oncogenic mutations of the Kit gene

  12. Kit Mutations in GISTs: • Familial: • Autosomal dominant transmission of constitutional, heterozygous, activating • Sporadic: • Exon 11 • Exon 9 • Exon 13 • Exon 17 Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34). 31461-31464

  13. GIST therapy: Gleevec • Gleevec more effective on GISTs caused by mutations in regulatory portion or protein than in the enzymatic region. • Gleevec targets active site of kinase. Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30). 31655-31663

  14. References • Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34). 31461-31464 • Reid, R.; de Silva, M.V.C. Pathology Oncology Research. 2003, 9 (1). 13-19. • Lasota, J. Miettinen, M. Arch. Pathol. Lab. Med. 2006, 130. 1466-1478. • Blume-Jensen, P. et al The EMBO Journal. 1991, 10 (13). 4121-4128. • Heinrich, M.C et al Human Pathology. 2002, 33 (5). 484-495. • Zhang, Z. PNAS .2002. 97, 7732-7737 • Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30). 31655-31663

  15. Questions? http://www.transmogrifier.org/ch/comics/search.cgi

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