Download Ret is a receptor tyrosine kinase

Ret tyrosine kinase
and multiple endocrine neoplasia
type 2 (MEN2)
Ret is a receptor tyrosine kinase
 The ret gene encodes a transmembrane protein tyrosine
kinase. It has an extracellular ligand-binding domain, a
cysteine-rich domain, and intracellular tyrosine kinase
domains.
 Associated with the cadherin superfamily
 Chromosomal locus 10q11.2
 Expressed in cells of neural crest origin
- in rodent embryonic and adult tissue, expressed in peripheral
enteric, sympathetic and sensory neurons, the excretory system
(mesonephric duct and branching ureteric bud during
embryogenesis)
Review: Receptor Tyrosine Kinases (RTKs)
 Receptor tyrosine kinases are involved in signaling in cell
growth, differentiation, survival, and apoptosis.
 In response to binding of extracellular ligands, RTKs generally
binding activates RTKs
form homodimers orLigand
heterodimers.
This is usually followed by
by dimerization
autophosphorylation and signal transduction through the pathway.
Ret Activation and Promotion of Signaling
Pathways
 Ligands are glial cell line-derived neurotrophic factor
(GDNF) family members
 Ligands bind glycosyl-phosphatidylinositol-anchored
coreceptors (GFR) 1-4
 Ret dimerizes as a result of activation by ligand/coreceptor
binding, autophosphorylates itself, and continues the
phosphorylation cascade.
 Among others, the GDNF/GFR1/RET complex initiates both
the RAS and PI3K pathways
- Pathways are activated through Tyr1062, which is a binding site for
SHC
- SHC further associates with GRB2/SOS and GAB1/2 complexes in
the Ras and PI3K pathways, respectively
Ret activation initiates PI3 Kinase and Ras pathways
Ligand = GDNF
Co-receptor = GFR-1
Wild-type Ras has multiple functions
 Development of the enteric nervous system (ENS) is primarily
dependent on GDNF/GFR1/RET
- loss of enteric ganglia if ret has a loss-of-function mutation
(Moore, M., et. al. (1996) Nature 382)
- c-ret homozygous mice develop an aganglionic phenotype and die
because of a lack of ganglia posterior to the stomach (Taraviras, S, et.al.
(1999) Development 126)
 Activation of the PI3K pathway by GDNF/GFR1/RET
blocks neuroectodermal apoptosis (Mograbi, B., et.al, (2001) J. Biol.
Chem. 276(48))
 Renal organogenesis
- GDNF/GFR1/RET null mice show renal agenesis and hypoplastic
kidneys due to lack of ureteric bud growth (Baloh, R.H, et.al. (2001) Curr.
Opin. Neurobiol. 10)
PI3K and Ras pathways interact in neural crest cells to
promote growth, differentiation, and survival
(Mograbi, B., et.al, (2001) J. Biol. Chem. 276(48))
Effects of Ret Mutations
Hirschsprung Disease (HSCR):
 A congenital absence of enteric innervation which results in intestinal
obstruction
 The mutations are varied and scattered throughout the Ret coding
sequence, which include deletions and a variety of point mutations
 This is the result of a loss-of-function mutation
Papillary Thyroid Carcinoma (PTC)
 RET/PTC oncoproteins in thyroid follicular cells, are frequently
found in radiation-induced papillary thyroid carcinomas
Multiple Endocrine Neoplasia (MEN) Type 2
 A group of cancer syndromes characterized by medullary thyroid
carcinoma
 This condition is the result of a gain-of-function mutation, causing
proliferation of thyroid cells
Multiple Endocrine Neoplasia Type 2
(MEN2)
 Rare familial cancer syndrome
 Usually germline mutations
 Autosomal dominant mode of inheritance
 Three types: FMTC (familial medullary thyroid carcinoma),
MEN2A, and MEN2B
 Affected cells are the C cells of the thyroid (these are derived
from neural crest cells)
 Medullary thyroid carcinomas are indicative of each type of
MEN2
- 75% of all MTCs are sporadic; the remainder are hereditary
- initially present as a mass on the neck or metastatic disease
FMTC
 patient presents with bilateral medullary thyroid carcinoma (MTC)
 Approximately 85% of families with FMTC have an identifiable
RET mutation
- Mutations occur at one of the five cysteine residues (codons 609, 611, 618, 620, and
634) with mutations of codons 618, 620, and 634 each accounting for 25 to 35% of
mutations.
 Presents at 20-40 years of age
 Believed to be more benign than MEN2A or B and prognosis is
good
MEN2A
 patient presents with MTC, pheochromocytomas (~50%) and/or
hyperparathyroidism (~15-30%)
 Approximately 95% of families with MEN 2A have a RET
mutation in exon 10 or 11
- Mutations of codon 634 Cys occur in about 85% of families; mutation of
cysteine residues at codons 609, 611, 618, and 620 together account for the
remainder of identifiable mutations in exons 10 and 11
 50% of individuals with mutations in the Ret gene develop the
disease by age 50, and 70% by age 70
 Most common form of MEN2, accounting for ~90% of all cases
MEN2B
 patient not only presents with MTC and bilateral
pheochromocytomas, but also with diffuse ganglioneuromas of the
intestinal tract, mucosal neuromas (on lips or tongue), and skeletal
abnormalities
 Approximately 95% of individuals with the MEN 2B phenotype
have a single point mutation in the tyrosine kinase domain of the
RET gene at codon 918 in exon 16, which substitutes a threonine for
methionine
 Accounts for ~5% of all MEN2 cases
 Age of onset is about 10 years earlier than of MEN2A, but
pheochromocytomas are sometimes detected in childhood
Ret mutations in MEN2
 Codon 634 mutations
render the RTK constitutively
active.
 This is a result of the
dimerization of the Ret
monomers due to the mutated
cysteine. The mutation leaves
an unpaired residue, and each
mutant Ret monomer forms a
disulfide bond with its
unpaired counterpart from
another mutant Ret.
 The same mechanism
applies to other mutations in
the cysteine-rich region of the
protein.
Detection and Treatment Options
 Ret testing, elevated calcitonin levels (produced in
C cells), elevated blood pressure if pheochromocytoma
is present
 Prophylactic thyroidectomy by age of 6 if mutation
is detected (by age of 3 if MEN2B is detected)
 Complete thyroidectomy after detection of MTC