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 Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30)

Old friend TFG-α Alberts et al. Fig

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

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

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

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

SCF-Kit essential for development of: Hematopoietic stem cells Mast cells Melanocytes Germ cells Interstitial cells of Cajal (ICC’s)

Mouse model  Constitutive activation  tumorigenic Kit is encoded by the mouse White locus (W) Mouse mutants :  Null (W -/-):  Pale  Died rapidly of anemia  Heterozygotes (W +/-):  Haploinsufficient  Phenotype varies with gene dosage (e.g. white spotting)  Lack network of ICC and ileum aperistaltic

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

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

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)

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

Gleevec targets activated form of Kit: Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34)

References Mol, C.D et al. Journal of Biological Chemistry. 2003, 278 (34) Reid, R.; de Silva, M.V.C. Pathology Oncology Research. 2003, 9 (1) Lasota, J. Miettinen, M. Arch. Pathol. Lab. Med. 2006, Blume-Jensen, P. et al The EMBO Journal. 1991, 10 (13) Heinrich, M.C et al Human Pathology. 2002, 33 (5) Zhang, Z. PNAS , Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30)

Questions?

In mice Null mutants neonatal lethal with anemia Null Heterozygotes or homozygotes for weak alleles have have less severe anemia, pigmentation defects, and sterility Kit disruption results in aperistalsis due to absence of functional ICC compartment