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c-kit

Katie Wilson. c-kit. History. Provirus Hardy-Zuckerman 4 feline sarcoma virus (v-kit) v-kit is the cellular homologue of c-kit. c-kit. Location – 4q12 Size – 976 amino acids 21 exons. What is c-kit?. -Transmembrane Receptor Tyrosine Kinase

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c-kit

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  1. Katie Wilson c-kit

  2. History • Provirus • Hardy-Zuckerman 4 feline sarcoma virus (v-kit) • v-kit is the cellular homologue of c-kit

  3. c-kit • Location – 4q12 • Size – 976 amino acids • 21 exons

  4. What is c-kit? -Transmembrane Receptor Tyrosine Kinase -encoded by dominant white spotting (W) locus -An oncogene

  5. What is c-kit? -Transmembrane Receptor Tyrosine Kinase -encoded by dominant white spotting (W) locus -An oncogene -Binds to stem cell factor (SCF) -This is encoded by Steel locus - activates Ras-Raf signaling pathway

  6. Signaling Pathway

  7. KIT is expressed on • Mast cells and Hematopoietic stem cells • Germ cells • Melanocytes

  8. Loss of function Mutations • Mast cells and Hematopoietic stem cells -anemia • Germ cells -Sterility • Melanocytes -Piebaldism

  9. Piebaldism

  10. Genetics • Weak mutations in c-kit cause white coat color, sterility, and anemia • Null mutations – embryonic lethal

  11. Gastrointestinal Stromal Tumors • 70% of GISTs develop in the stomach • 20% in the small intestine • <10% in the esophagus, colon, and rectum Around 5,000 to 6,000 new cases each year of GIST

  12. ICC and GIST • Interstitial cells of Cajal, pacemaker cells, regulate the gut movement • ICC expressed c-kit • Tumors arise from ICC

  13. c-kit is mutated in Gastrointestinal Stromal Tumors • in-frame deletions and point mutations in exon 11 • Mutations found in the cytoplasmic domains of c-kit receptor • Occur in patients 40-70 years old

  14. Mutation • Ligand-independent tyrosine kinase activity • Autophosphorylation of KIT • Uncontrolled cell proliferation • Stimulation of downstream signaling pathways (Ras-Raf)

  15. C-kit

  16. Therapy: Kinase inhibitor

  17. Summary • c-kit is a tyrosine kinase receptor • Dominant negative mutation • Signals Ras-Raf pathway • c-kit mutations found in GISTs

  18. Sources Botchkareva, Natalia. SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. 2001 The FASEB Journal 15:645-658. Goding, Colin. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage. 2000 Genes and Development 14(14):1712-28. Heinrich, MC. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations 2002 Human Pathology 33(5):484-95. Hemesath, Timothy. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. 1998 Nature 391:298-301. Kapur, Reuben. Signaling Through the Interaction of Membrane-Restricted Stem Cell Factor and c-kit Receptor Tyrosine Kinase: Genetic Evidence for a Differential Role in Erythropoiesis. 1998 Blood 91(3):879-889. Mackenzie, Marina. Activation of the Receptor Tyrosine Kinase Kit is Required for the Proliferation of Melanoblasts in the Mouse Embryo. 1997 Developmental Biology 192: 99-107. Mol, Clifford. Structure of a c-kit Product Complex Reveals the Basis for Kinase Transactivation. 2003 The American Society for Biochemistry and Molecular Biology C300186200. Moskaluk, CA. Mutations of c-kit JM domain are found in minority of human gastrointestinal stromal tumors. 1999 Nature 18(10):1897-1902. Wardelmann, Eva. C-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epitheliod Cell Variant. 2002 Modern Pathology 15(2):125-136.

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