1 / 11

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.

lael-murray
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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)

More Related