1. Ishita Das http://www.umm.edu/endocrin/anatomy.htm

2.  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)

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

4. 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)

5.  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

6.  RET and co-receptor were both knocked out  defects in early hindgut and kidney formation  RET with mutated TK domain gave same results

7.  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

8.  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

9.  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)

10.  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)

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

12.  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/Follicul ar_Thyroid_Carcinoma_a445_f39.html

13.  tyrosine kinase inhibitor ZD6474 blocks oncogenic RET kinases  Zactima ® : around 30% remissions Wells et al. Annu Rev Med. (2007)

14.  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