RET
description
Transcript of RET
RETProto-Oncogene of Multiple Endocrine Neoplasia type
2(MEN2)
What is RET? Codes for a RTK On chromosome 10 21 exons “Rearranged during Transfection”
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
RET protein function signaling to a variety of pathways, most
notably the Ras signaling pathway and the phosphatidylinositol-3 kinase pathway.
The ultimate biological effects:
morphological changes in the cytoskeleton, cell scattering, proliferation, and differentiation.
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
RET protein structure N-terminal signal peptide Cadherin domain Cysteine rich region TK domain C-terminal; different isoforms for different
functions
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
How is RET normally activated? Ligands:
GDNF – glial derived neutrotrophic factor
NTN – neurturin PSP – persephin Artemin
Co-receptors GFR 1, 2, 3 and 4
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
Ligand Binding
How is RET normally activated?1) RTK signalling induced by ligand
oligomerization2) Tyrosine autophosphorylation3) Ca+2-dependent extracellular cadherin
domain
Manie et al. http://tig.trends.com
Ligand binding
Manie et al. http://tig.trends.com
RET activating pathways
Normal RET functions TK receptor for GDNF, NTN, PSP and
Artemin Expressed in
Neural crest Urogenital precursor cells
Required for Kidney morphogenesis Neuron maturation Spermatogonia maturation
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
Knockout Mutation
RET-null mice
Transgenic mice without functional RET or its co-receptors showed defective enteric growth and ureteric budding
Manie et al. http://tig.trends.com
Kidney morphogenesis
Manie et al. http://tig.trends.com
Recent Finding: RET apoptotic activity RET to induce apoptosis in the absence of
GDNF Is ligand-independent Molecular mechanisms unknown
Manie et al. http://tig.trends.com
Summary: Normal RET activation1) Calcium-dependent ligand binding2) Autophosphorylation of Tyrosine residues3) Activation of proliferation pathways4) Cell growth and differentiation
Carcinomas Caused by RET mutations Papillary Thyroid Carcinoma (PTC) Medullary Thyroid Carcinomas (MTC)
Multiple Endocrine Neoplasia type 2 (MEN2) A,B
Famillilar Medullary Thyroid Carcinoma (FMTC) Hirschsprung disease
Manie et al. http://tig.trends.com
Mutations
Manie et al. http://tig.trends.com
Carcinomas
RET in PTC Rearrangements of RET tyrosine kinase
coding region with unrelated genes = PTC
Medullary Thyroid Carcinomas (MTCs) Facts
Thyroid C cells are derived from neural crest 75% are sporadic Remainding are inherited forms of MEN2
Activating mutations of RET
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
MEN2A Mutations in cysteine-rich extracellular
domain of RET 80% of these mutations are exchange of a
cysteine for arginine Leaves unpaired cysteine residue, loss of
intramolecular dissulfide bond, and an available intermolecular dissulfide bond with other mutant RET receptors.
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
Disulfide bond interactions
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
MEN2B 95% are mutations in M918T (exon 16)
Usually paternal 5% mutations in RET TK domain
Changes substrate binding, RET phosphorylation of proteins, and RET autophosphorylation
Alberti et al., Journal of Cellular Physiology. 195: 168-186 (2003)
MEN2 Treatment Good prognosis with early detection Thryoidectomy early
Removal of thyroid gland RET oncoprotein inhibitors
ZD6474 Pyrazolo-pyrimidine (PP2)
ZD6474: Oral inhibitor In vivo
Blocked phosphorylation of PTC3 and MEN2B oncoproteins
Blocked EGF receptor Reverted some PTC cells
http://cancerres.aacrjournals.org/cgi/content/full/62/24/7284
PP2 Blocked kinase activity of PTC1
oncoproteins Prevented serium growth of PTC cells Hopeful for MTC therapy
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12679489&dopt=Abstract
Sources Alberti et al., Journal of Cellular Physiology. 195:
168-186 (2003) Manie et al. http://tig.trends.com http://www.ncbi.nlm.nih.gov/entrez/
query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12679489&dopt=Abstract
http://cancerres.aacrjournals.org/cgi/content/full/64/24/7284.com
http://www.ohiolink.edu/etd/send-pdf.cgi?osu970163275