c-kit katie wilson. history provirus hardy-zuckerman 4 feline sarcoma virus (v-kit) v-kit is the...
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c-kit
Katie Wilson
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HistoryProvirus
Hardy-Zuckerman 4 feline sarcoma virus (v-kit)
v-kit is the cellular homologue of c-kit
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c-kitLocation – 4q12 Size – 976 amino acids
21 exons
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What is c-kit?-Transmembrane Receptor Tyrosine
Kinase-encoded by dominant white spotting (W)
locus-An oncogene
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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
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Signaling Pathway
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KIT is expressed on Mast cells and Hematopoietic stem cells
Germ cells
Melanocytes
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Loss of function Mutations Mast cells and Hematopoietic stem cells
-anemiaGerm cells -SterilityMelanocytes
-Piebaldism
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Piebaldism
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Genetics
Weak mutations in c-kit cause white coat color, sterility, and anemiaNull mutations – embryonic lethal
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Gastrointestinal Stromal Tumors
70% of GISTs develop in the stomach20% in the small intestine<10% in the esophagus, colon, and rectum
Around 5,000 to 6,000 new cases each year of GIST
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ICC and GISTInterstitial cells of Cajal, pacemaker cells, regulate the gut movement
ICC expressed c-kit
Tumors arise from ICC
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c-kit is mutated in Gastrointestinal Stromal
Tumorsin-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
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MutationLigand-independent tyrosine kinase activity
Autophosphorylation of KIT
Uncontrolled cell proliferation
Stimulation of downstream signaling pathways (Ras-Raf)
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C-kit
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Therapy: Kinase inhibitor
Structure of Imatinib
(4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[{4-(3-pyridinyl)-2-pyrimidinyl}amino] phenyl]benzamide methanesulfonate.
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Summaryc-kit is a tyrosine kinase receptor
Dominant negative mutation
Signals Ras-Raf pathway
c-kit mutations found in GISTs
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SourcesBotchkareva, 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.