Ishita Das

http://www.umm.edu/endocrin/anatomy.htm

RET = REarranged during Transfection

Proto-oncogene that codes for a transmembrane RTK

chromosome 10 RET gene was discovered in

1985 RET ligand was found in 1996

GDNF (glial cell derived neurotrophic factor) family of ligands

Each RET kinase has a co-receptor (GFRα) to which the ligand binds Jing et al. (1996)

Drosten and Pützer, Nat Clin Pract Oncol (2006)

How RET affects signal pathways ligand binds to RET dimerization of the extracellular domain TK domain phosphorylates tyrosine residues of the intracellular

domain RET activates the MAP Kinase pathway (cell growth, survival,

and migration) RET becomes ubiquitinated and degrades

Alberti et al. Journal of Cell Physiology (2003) Zbuk and Eng, Nature (2007)

RET signaling crucial for development of enteric nervous system

RET is present in sympathetic, parasympathetic, motor, and sensory neurons of the enteric nervous system

Kidney development spermatogenesis

RET and co-receptor were both knocked out defects in early hindgut and kidney formation

RET with mutated TK domain gave same results

Hirschsprung’s disease: loss-of-function mutation

Papillary thyroid cancer MEN2 cancer syndromes

MEN2A: papillary thyroid carcinoma, adrenal gland cancer, parathyroid gland cancer, medullary thyroid carcinoma (MTC)

MEN2B: MTC, thyroid and adrenal tumors, ganglion nerve cell tumors in the intestinal tract

FMTC

Autosomal dominant inheritance 1 in 30,000 of general population Very high penetrance but variable expressivity Germline gain-of-function mutation Characterized by MTC Most often bilateral and therefore occurs in

patients at an early age Some sporadic MTC Children with inherited mutant RET allele can

have a prophylactic thyroidectomy

80% of cases of MEN2 Germline point mutations of cysteine-rich extracellular

domain: converts cysteine to another amino acid disulfide bond to another mutant RET Ligand independent dimerization and constitutive kinase

activity

Alberti et al. Journal of Cell Physiology (2003)

5% of cases of MEN2 Germline point mutations in

TK domain Constitutive kinase activity

with decreased substrate specificity

Converts the substrate-binding pocket of RET

FMTC: 15% of cases of MEN2-mutations in extra and intracellular domains

Rubeberg-Roos and Saarama, Annals of Medicine (2007)

Drosten and Pützer, Nat Clin Pract Oncol. (2006)

MTC causes death Early genetic screening C cells of thyroid are

precursors of MTC because they secrete calcitonin

Treatment of hereditary or sporadic is total thyroidectomy with regional lymphadenectomy

http://www.steadyhealth.com/articles/Follicular_Thyroid_Carcinoma_a445_f39.html

tyrosine kinase inhibitor ZD6474 blocks oncogenic RET kinases

Zactima® : around 30% remissions

Wells et al. Annu Rev Med. (2007)

RET is a proto-oncogene that codes for a transmembrane RTK

extracellular cysteine rich domain and an intracellular TK domain

RET uses a co-receptor to bind to ligands and activates many signal pathways

MEN2A results because of ligand independent dimerization

MEN2B results because of mutations in the kinase domain

Treatments being researched for MTC