c-kit

Katie Wilson

HistoryProvirus

Hardy-Zuckerman 4 feline sarcoma virus (v-kit)

v-kit is the cellular homologue of c-kit

c-kitLocation – 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

-anemiaGerm cells -SterilityMelanocytes

-Piebaldism

Piebaldism

Genetics

Weak mutations in c-kit cause white coat color, sterility, and anemiaNull mutations – embryonic lethal

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

ICC and GISTInterstitial cells of Cajal, pacemaker cells, regulate the gut movement

ICC expressed c-kit

Tumors arise from ICC

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

MutationLigand-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-[4-methyl-3-[{4-(3-pyridinyl)-2-pyrimidinyl}amino] phenyl]benzamide methanesulfonate.

Summaryc-kit is a tyrosine kinase receptor

Dominant negative mutation

Signals Ras-Raf pathway

c-kit mutations found in GISTs

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.