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

Mol, C.D et al. Journal of Biological Chemistry. 2004, 279 (30). 31655-31663

Old friend TFG-α

Alberts et al. Fig. 15-48

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 .2002. 97, 7732-7737

SCF-Kit


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://

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

http://www.nature.com/jid/journal/v126/n5/images/5700315i3.jpg

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


GIST therapy: Gleevec


Gleevec targets active site of kinase.

Gleevec more effective on GISTs caused by mutations in regulatory portion or protein than in the enzymatic region.

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

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c-Kit

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