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C-Kit: function and role in normal cells and GISTs. Tyler Downey. KIT Structure. C-kit encodes KIT, a Cytokine Receptor Receptor Tyrosine Kinase (RTK) KIT Ligand – Stem Cell Factor (SCF). D. Linnekin / The International Journal of Biochemistry & Cell Biology. KIT Activation. - PowerPoint PPT Presentation
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C-Kit: function and role in normal cells and GISTs
Tyler Downey
KIT Structure
• C-kit encodes KIT, a Cytokine Receptor– Receptor Tyrosine Kinase
(RTK)
• KIT Ligand – Stem Cell Factor (SCF)
D. Linnekin / The International Journal of Biochemistry & Cell Biology
KIT Activation
• Homodimerization
• Increased auto-phosphorylation
• Kinase domain activation
Heinrich et al, Human Pathology Volume 33, No. 5 (May 2002)
Kit Molecular Pathways
- Pathways Activated:• Src Family• Ras• PI-3 Kinase Family• JAK/STAT Family-KIT Inhibition Pathways:• SHP1 & SHP2
D. Linnekin / The International Journal of Biochemistry & Cell Biology
Where is KIT expressed?LacZ mice
• Mice embryos express WLacZ mutation on c-kit• Breed WLacZ/WLacZ and WLacZ/+ mice and look for
β-gal-positive cells
F. Bernex et al Development 122, 3023-3033 (1996)
2 forms of KIT expression in embryogenesis
• KIT expressed but not essential for survival/proliferation/migration
• Endothelial cells, endocrine cells, Interstitial cells of cajal (ICC)
• KIT expression essential for survival/proliferation/migration
• Melanoblasts, Primordial Germ Cells (PGC), hematopoietic progenitors
Cellular Responses to KIT
• Survival• Proliferation• Migration• Differentiation• Adhesion
•main forms of KIT function:
- c-kit function essential during
embryogenesis
- c-kit function essential in post-natal
tissues
KIT in Cancer
• Gastrointestinal Stromal Tumors (GISTs)– Most common mesenchymal tumors of digestive
tract.– Constitutively activated KIT mutants found in over
90% of GISTs– GISTs form from Interstitial Cells of Cajal (ICC)
• Expresses c-kit and CD34, same as GIST tumors
• Kit expression also found in seminomas, and leukemia
Interstitial Cells of Cajal (ICC)
• Pacemakers of intestine– Cause smooth muscle
contraction of the intestine• ICC precursors require c-kit for
differentiation• Only cell type in intestine to
normally express c-kit and CD34– C-kit and CD34 both expressed
in GIST
T. Komuro J Physiol 576.3 (2006)
C-kit Role in GIST
• Early KIT oncogenic expression pivotal in GIST tumorigenesis
• KIT mutation alone causes ICC hyperplasia
• Chromosome deletions follow KIT mutation
Forms of KIT mutation• 2 forms of KIT mutation
– Mutation of regulatory region of KIT• Most common in juxtamembrane region of KIT
– Mutation of Kinase region of KIT
• Some constitutively activated KITs may have altered signaling pathway
Heinrich et al, Human Pathology Volume 33, No. 5 (May 2002)