1. c-kit
Katie Wilson

2. History Provirus v-kit is the cellular homologue of c-kit
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
In mice – inhibitory c-kit antibody leads to loss of function of ICC and impaired gut movement
Melanocytes - Piebaldism

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 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 The FASEB Journal 15:
Goding, Colin. Mitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage Genes and Development 14(14):
Heinrich, MC. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations 2002 Human Pathology 33(5):
Hemesath, Timothy. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes Nature 391:
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 Blood 91(3):
Mackenzie, Marina. Activation of the Receptor Tyrosine Kinase Kit is Required for the Proliferation of Melanoblasts in the Mouse Embryo Developmental Biology 192:
Mol, Clifford. Structure of a c-kit Product Complex Reveals the Basis for Kinase Transactivation The American Society for Biochemistry and Molecular Biology C
Moskaluk, CA. Mutations of c-kit JM domain are found in minority of human gastrointestinal stromal tumors Nature 18(10):
Wardelmann, Eva. C-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epitheliod Cell Variant Modern Pathology 15(2):