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RET Receptor

RET Receptor. Ashley Bass. What is RET?. 10q11.2 21 exons Transmembrane Receptor Tyrosine Kinase Oncogene. http://ghr.nlm.nih.gov. RET Schematic. De Groot et al. 2006. What does it do?. Important in kidney and neural development Expressed in neural crest cells

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RET Receptor

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  1. RET Receptor Ashley Bass

  2. What is RET? • 10q11.2 • 21 exons • Transmembrane Receptor Tyrosine Kinase • Oncogene http://ghr.nlm.nih.gov

  3. RET Schematic De Groot et al. 2006

  4. What does it do? • Important in kidney and neural development • Expressed in neural crest cells • Proliferation, differentiation, growth and cell survival via RAS and PIK3 pathways

  5. Activation of RET De Groot et al. 2006

  6. http://www.cnio.es/ing/grupos/plantillas/presentacion.asp?pag=254http://www.cnio.es/ing/grupos/plantillas/presentacion.asp?pag=254

  7. De Groot et al. 2006

  8. De Groot et al. 2006

  9. De Groot et al. 2006

  10. Knock Out Mice • Die shortly after birth • Renal agenesis or severe dysgenesis • Absence of enteric neurons

  11. Kidney Defects in RET Mutant Mice Schuchardt et al. 1994

  12. RET & Human Disease • Loss of Function • Hirschprung’s Disease

  13. Hirschprung’s Disease • Absence of enteric neurons • No peristalsis in GI tract • Missense/nonsense mutation • 1/5,000 live births • Inherited and sporadic • Treatment

  14. RET & Human Disease • Loss of Function • Hirschprung’s Disease • Chromosomal Rearrangements • Germline Mutations • Gain of Function • Multiple Endocrine Neoplasia Type II • Familial Medullary Thyroid Carcinoma

  15. Multiple Endocrine Neoplasia Type II • Affects thyroid, parathyroid, and adrenal glands • Autosomal Dominant • 70% Penetrant • 1/30,000 affected • Point mutations in germline • Treatment – removal of thyroid • Good prognosis with early diagnosis and intervention

  16. Type IIA Tumor Formation –parathyroid Hyperparathyroidism Mutation in cysteine region Later onset Less severe Type IIB Tumor Formation –mucosal neuromas Oral cavity, GI tract Mutation in tyrosine kinase domain Earlier onset More aggressive More rare MEN Type IIA vs. IIB

  17. Mucosal Neuromas www.valleyhealth.com

  18. Familial Medullary Thyroid Carcinoma • Extracellular or TK domain mutations • Results in lower transforming activity • Predisposition to FMTC instead of MEN 2A • Benign Tumors of adrenal glands and parathyroid

  19. Summary of RET Receptor • Transmembrane receptor tyrosine kinase • Involved in renal and neural development • Thyroid Carcinoma • Multiple Endocrine Neoplasia Type II • Familial Medullary Thyroid Carcinoma

  20. References • Alberti et al. “RET and NTRK1 proto-oncogenes in human diseases.” Jour. of Cellular Physiology. 195:168-186 (2003). • De Groot et al. “RET as a diagonostic and therapeutic target in sporadic and hereditary endocrine tumors.” Endocrine Reviews. 27(5): 535-560. • Ichihara et al. “RET and neuroendocrine tumors.” Cancer Letters. 204:197-211 (2004). • Manie et al. “The RET receptor: function in development and dysfunction in congenital malformation.” TRENDS in genetics. 17.10:580-589 (2001). • Schuchardt et al. “Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.” Nature. 367:380-383 (1994). • Weinberg, Robert. The Biology of Cancer. New York: Garland Science, 2007.

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