Download REarranged

Ishita Das
http://www.umm.edu/endocrin/anatomy.htm
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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
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Each RET kinase has a coreceptor (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
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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
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RET and co-receptor were both
knocked out  defects in early
hindgut and kidney formation
 RET with mutated TK domain
gave same results
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Hirschsprung’s disease: loss-of-function
mutation
 Papillary thyroid cancer
 MEN2 cancer syndromes
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 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
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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
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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 substratebinding pocket of RET
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Rubeberg-Roos and Saarama,
Annals of Medicine (2007)
FMTC: 15% of cases of MEN2
-mutations in extra and intracellular domains
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
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http://www.steadyhealth.com/articles/Follicul
ar_Thyroid_Carcinoma_a445_f39.html
tyrosine kinase inhibitor ZD6474 blocks
oncogenic RET kinases
 Zactima® : around 30% remissions
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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
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