Download C-kit

c-kit
Katie Wilson
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
-encoded by dominant white spotting (W) locus
-An oncogene
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
Signaling Pathway
KIT is expressed on
Mast cells and Hematopoietic stem cells
Germ cells
Melanocytes
Loss of function Mutations
Mast cells and Hematopoietic stem cells
-anemia
Germ cells
-Sterility
Melanocytes
-Piebaldism
Piebaldism
Genetics
Weak mutations in c-kit
cause white coat color,
sterility, and anemia
Null mutations – embryonic
lethal
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
ICC and GIST
Interstitial cells of Cajal, pacemaker
cells, regulate the gut movement
ICC expressed c-kit
Tumors arise from ICC
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
Mutation
Ligand-independent tyrosine kinase activity
Autophosphorylation of KIT
Uncontrolled cell proliferation
Stimulation of downstream signaling
pathways (Ras-Raf)
C-kit
Therapy: Kinase inhibitor
Structure of Imatinib
(4-[(4-methyl-1-piperazinyl)methyl]-N-[4methyl-3-[{4-(3-pyridinyl)-2pyrimidinyl}amino] phenyl]
benzamide methanesulfonate.
Summary
c-kit is a tyrosine kinase receptor
Dominant negative mutation
Signals Ras-Raf pathway
c-kit mutations found in GISTs
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: 99107.
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.