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C-Kit: function and role in normal cells and GISTs

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.

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C-Kit: function and role in normal cells and GISTs

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  1. C-Kit: function and role in normal cells and GISTs Tyler Downey

  2. 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

  3. KIT Activation • Homodimerization • Increased auto-phosphorylation • Kinase domain activation Heinrich et al, Human Pathology Volume 33, No. 5 (May 2002)

  4. 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

  5. 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)

  6. 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

  7. Cellular Responses to KIT • main forms of KIT function: • - c-kit function essential during embryogenesis • - c-kit function essential in post-natal tissues • Survival • Proliferation • Migration • Differentiation • Adhesion

  8. 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

  9. 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)

  10. C-kit Role in GIST • Early KIT oncogenic expression pivotal in GIST tumorigenesis • KIT mutation alone causes ICC hyperplasia • Chromosome deletions follow KIT mutation

  11. 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)

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