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FLASH GENE

Symbol

RET

contributors: npt/mct - updated : 24-02-2018

HGNC name	ret proto-oncogene
HGNC id	9967

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CCHS1 congenital central hypoventilation syndrome HSCR1 Hirschsprung disease 1 MEN2A endocrine neoplasia, multiple, type IIA MEN2B endocrine neoplasia, multiple, type IIB, allelic to MEN2A MTC1 familial and sporadic medullary thyroid carcinoma PTC1 PTC1 chimeric oncogene RADP renal adysplasia
Location	10q11.21      Physical location : 43.572.516 - 43.625.795
Synonym name	ret proto-oncogene, rearranged during transfection (see HSCR2, MEN2A, MEN2B, MTC1)
	ret proto-oncogene
	cadherin family member 12
	proto-oncogene tyrosine-protein kinase receptor Ret
	RET transforming sequence
	hydroxyaryl-protein kinase
Synonym symbol(s)	GDNFR, CDHF12, RET51, CDHR16, RET-ELE1, HSCR1, MEN2A, MEN2B, MTC1, PTC-ELE1, RET5
EC.number	2.7.1.112, 2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	53.28 kb     20 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

Map

see RBP3

RNA

TRANSCRIPTS	type	messenger

text	alternatively spliced at its 3 prime end to produce multiple protein isoforms (PMID: 22875993)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_020975 20 splicing 5629 NP_066124 124.32 1114 is efficiently matured and present in relatively higher amounts on the plasma membrane 2010 20442138 also called variant 2/isoform a or RET51 composed of an extracellular binding domain, a hydrophobic transmembrane domain and a cytoplasmic portion with the TK and pro-apoptotic domain not present until later stages of human development activated by NGF in mature sympathetic neurons role for the RET51–FKBP4 complex in adult neurons of the central nervous system NM_020630 19 splicing 4174 NP_065681 120 1072 immature RET9 accumulates intracellularly in the Golgi 2010 20442138 also called variant 7/isoform c or RET9 RET9 C-terminal amino acid tail, within the context of its normal upstream sequences, is responsible for the retention of this isoform within the Golgi apparatus NM_001355216 - splicing 3674 NP_001342145 - 818 - 2010 20442138

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine adrenal gland       highly Nervous ganglia autonomic ganglia     highly   ganglia sensory ganglia dorsal root   highly Reproductive female system breast mammary gland   highly Visual eye retina fovea       eye retina macula       eye uvea choroid

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier lining retinal pigment epithelium (RPE)

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	the developing kidney, the presumptive enteric neuroblats,cranial ganglia (VII,VIII,IX and X) and in the presumptive motor neurons of the spinal cord

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an extracellular cadherin domain with four cadherin-like domains and a cysteine-rich domain
	a single transmembrane (1TM) segment
	a cytoplasmic bipartite tyrosine kinase domain (see also RFP5RET)

mono polymer

homomer , dimer

HOMOLOGY

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family

CATEGORY

enzyme , protooncogene , receptor membrane tyrosine kinase

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endosome

basic FUNCTION	potentially involved in peripheral nerve repair
	inducer of apoptosis
	canonical signaling receptor for glial cell line-derived neurotrophic factor (GDNF), having neuroprotective effects when administered prior to neurotoxic challenge
	RET signaling is protective for dopaminergic cell bodies but not for axonal terminals
	having a critical role in the development of the enteric nervous system (ENS), parasympathetic nervous system and kidney
	functional role of RET51/FKBP4 complex in dopaminergic neurons and possibly in the pathogenesis of Parkinson disease
	its expression in dorsal root ganglion neurons is crucial for the neurturin-mediated formation of precise axonal projections in the central nervous system
	after ligand binding induces dimerization, activates multiple signal transduction pathways
	important role of intracellular trafficking in modulating and maintaining RET signaling
	playing a key role during embryogenesis and in particular during the enteric nervous system development
	putative functional role of the RET gene in modulating immune cell responses during inflammation and carcinogenesis
	activation of RET results in improved haematopoietic stem cell survival, expansion and in vivo transplantation efficiency

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

receptor tyrosine kinase pathway

a component

component of glial cell line derived neurotrophic factor (GDNF) receptor, homodimerizing and binding the GDNF-GFRA complex

INTERACTION

DNA

RNA

small molecule

protein	interacting with SHC1 transduction adaptor protein
	interacting with GDNF and GFRA1, by its extracellular domain
	CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with RET under basal, unstimulated conditions in neurons
	CBLC interacts with unphosphorylated RET and dissociates from RET after RET activation
	transcriptional target of NR4A2
	involvement of a novel interaction of RET with RAP1GAP in the regulation of GDNF-mediated neurite outgrowth
	interacting with ITGB1 (can activate ITGB1, and that RET-induced cell adhesion and migration require ITGB1)
	caspase cleavage of RET is involved in the regulation of adhesion in sympathetic neurons
	HOXB5 binds to the promoter region 5prime upstream of the binding site of NKX2-1 and regulates RET expression
	HOXB5 in coordination with other transcription factors mediates RET expression
	GDNF restores human blood-nerve barrier function via RET tyrosine kinase-mediated cytoskeletal reorganization
	TOP2A, TOP1 are involved in initiating aphidicolin-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication
	PDLIM7 is a CBLC interacting protein, and binding of PDLIM7 to RET prevents CBLC recruitment to RET
	HOXB5 regulates RET transcription, and perturbations in transcriptional regulation by HOXB5 caused reduced RET expression and defective enteric nervous system development
	low-frequency alterations such as EIF4G1 might participate in RET-associated tumorigenesis, possibly by regulating the activity of the RET pathway
	dual kinase function of the RET proto-oncogene negatively regulates ATF4-mediated apoptosis
	interaction between the atypical cadherin FAT4 and RET, a tyrosine kinase receptor essential for kidney development

cell & other

REGULATION

induced by

by NR4A2 (induced the transcription of the RET promoter in cell type and concentration-dependent manner)

inhibited by

pro-apoptotic effect inhibited by its ligand GDNF

Other	regulation by acidification of the Golgi apparatus that is crucial for maturation of RET but not indispensable for trafficking of receptors to the membrane
	dys-regulation of RET expression by HOXB5 could result in insufficient RET expression and Hirschsprung disease

ASSOCIATED DISORDERS

corresponding disease(s)

CCHS1 , HSCR1 , MEN2A , MEN2B , MTC1 , PTC1 , RADP

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       fused with NCOA4 in papillary thyroid carcinoma tumoral   deletion     in small cell lung cancer tumoral   amplification     in thyroid, parathyroid, adrenal tumor tumoral       gain of function underlies the genesis and progression of multiple endocrine neoplasia type 2 tumoral fusion       fused with HOOK3 in papillary thyroid carcinoma (Ciampi 2007) tumoral   translocation     5'- TRIM24 - RET -3' fused in papillary thyroid carcinoma (see PTC6) tumoral fusion       KIF5B-RET fusion promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling tumoral imprinting       aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation, and that RET can serve as a tumor suppressor gene in the colon (

Susceptibility

to Hirschsprung, short segment(HSCR) to renal aplasia

Variant & Polymorphism SNP , other	CI35AIA in short segment Hirschsprung's disease
	A-C-A haplotype overrepresented in Hirschsprung disease and associated with reduced gene expression
	a common sex-dependent mutation in a enhancer increasing the risk of HSCR
	a common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease
	frequent mutation associated to renal aplasia
	SNP1 (rs2506004) and SNP2 (rs 2435357)] have been shown to be etiologically important in the pathogenesis of Hirschsprungdisease (HSCR)

Candidate gene
Marker
Therapy target	Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations including RET and have shown efficacy against a variety of malignancies
	System Type Disorder Pubmed cancer     small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations including RET and have shown efficacy against a variety of malignancies cancer reproductive breast inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer

ANIMAL & CELL MODELS

RET conditional knock-out mice are characterized from a late and progressive degeneration of dopaminergic (DA) neurons