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.