Download - 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 Proliferation, differentiation, growth
and cell survival via RAS and PIK3 pathways
Activation of RET
De Groot et al. 2006
http://www.cnio.es/ing/grupos/plantillas/presentacion.asp?pag=254
De Groot et al. 2006
De Groot et al. 2006
De Groot et al. 2006
Knock Out Mice
Die shortly after birth Renal agenesis or severe
dysgenesis Absence of enteric neurons
Kidney Defects in RET Mutant Mice
Schuchardt et al. 1994
RET & Human Disease
Loss of Function Hirschprung’s Disease
Hirschprung’s Disease
Absence of enteric neurons No peristalsis in GI tract Missense/nonsense mutation 1/5,000 live births Inherited and sporadic Treatment
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
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
MEN Type IIA vs. IIB
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
Mucosal Neuromas
www.valleyhealth.com
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
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
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.