RET

RET

Proto-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.


RET protein structure N-terminal signal peptide Cadherin domain Cysteine rich region TK domain C-terminal; different isoforms for different

functions


How is RET normally activated? Ligands:

GDNF – glial derived neutrotrophic factor

NTN – neurturin PSP – persephin Artemin

Co-receptors GFR 1, 2, 3 and 4


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


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


Knockout Mutation

RET-null mice

Transgenic mice without functional RET or its co-receptors showed defective enteric growth and ureteric budding


Kidney morphogenesis


Recent Finding: RET apoptotic activity RET to induce apoptosis in the absence of

GDNF Is ligand-independent Molecular mechanisms unknown


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


Mutations


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


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.


Disulfide bond interactions


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


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

Documents

RET