c-KIT and Gastrointestinal Stromal Tumors (GISTs)

1. c-KIT and Gastrointestinal Stromal Tumors (GISTs) Stefanie Chua 30 March 2004

2. What is KIT? • Transmembrane type III tyrosine kinase receptor • c-KIT is the cellular homologue of v-KIT • Maps to chromosome 4 (4q11-12)

3. Where is KIT found? • Hematopoietic stem cells • Mast cells • Melanocytic cells • Germ cells • Gametophytes • **Interstitial cells of Cajal (ICC)

4. Structure of KIT • Extracellular domain • Transmembrane domain • Intracellular domain • Mutations are typically found in the kinase domain

5. Ligand: SCF • Ligand for KIT: stem cell factor (SCF) or Steel • It is found on… • bone marrow stroma cells • Fibroblasts • Keratinocytes • intestinal epithelial cells • Sertoli’s cells • granulosa cells

6. KIT Activation

7. Knockout Mice • Homozygous recessive mouse: dies within days because of macrocytic anemia • Heterozygous mouse: defect in pigmentation with white spotting phenotype, piebaldism.

8. KIT mutation • Like most RTKs, KIT kinase has multiple levels of control, therefore, a number of phenotypic changes are observed because KIT is found in a number of different cells including stem and germ cells. • These types of mutations result in a loss of kinase function. • BUT… gain of function mutations are involved in the induction of tumors of ICCs to form GISTs

9. KIT and SCF • Heterozygous for a loss of function mutation • Only have half of the normal amount of KIT gene product • Shortage of red blood cells • Shortage of pigment cells • Shortage of germ cells

10. Gastrointestinal Stromal Tumors (GISTs) • GISTs develop from ICCs • GISTs and ICCs are double positive for KIT and CD34.

11. GISTs in relation to KIT • 84 – 100% of GISTs express constitutively active KIT • KIT oncogenic activation occurs in the early stages of benign GIST formation • Not dependent on binding of KIT ligand • Have structural changes that favor receptor oligomerization and cross phosphorylation even in the absence of ligand • When mutation occurs in KIT, the tyrosine kinase activity of KIT is constitutively gained without the binding of SCF.

12. Treatment: Gleevac • Chemotherapy and radiation are not conducive to the treatment GISTs • It was found that KIT oncoproteins have the same active enzymatic site as native KIT. Therefore, kinase inhibitors like STI-571 (Gleevac)bind well and are effective inhibitors of constitutively activated molecules.

13. Works Cited Hirota S. Gastrointestinal stromal tumors: their origin and cause. [Review] International Journal of Clincal Oncology. 6(1): 1-5, 2001 Feb. Taylor ML. Metcalfe DD. Kit signal transduction [Review] Hematology – Oncology Clinics of North America. 14(3): 517-25, 2000 Jun. Heinrich MC. Rubin BP. Longle BJ. Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. [Review] Human Pathology. 33(5): 484 –95, 2002 May. Ashman LK. The biology of stem cell factor and its receptor C-kit. [Review] International Journal of Biochemistry and Cell Biology. 31(1999): 1037-1051, 1999 Feb. Longley BJ. Reguera MJ. Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. [Review] Leukemia Research. 25(2001): 571-576, 2001 Jan. Waskow C. Rodewald HR. Lymphocyte development in neonatal and adult c-Kit-deficient mice. [Review] Advances in Experimental Medicine and Biology. 512:1-10, 2002. Gilbert, Scott F. Developmental Biology, 7th ed. 2003: USA. Sinauer Associates, Inc.