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FLASH GENE
Symbol RET contributors: npt/mct - updated : 24-02-2015
HGNC name ret proto-oncogene
HGNC id 9967
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
    Physical map
    LOC389953 10 similar to Ig kappa chain V region (Z4) - human LOC389954 10 similar to poly(A) binding protein, cytoplasmic 1 LOC389955 10 similar to Zinc finger protein 43 (Zinc protein HTF6) (Zinc finger protein KOX27) MGC16291 10q11.21 hypothetical protein MGC16291 LOC389956 10 similar to ZNF37A protein LOC387659 10 LOC387659 LOC143341 10q11.21 eukaryotic translation initiation factor 3, subunit 6 interacting protein, putative pseudogene ZNF11B 10q11.2 zinc finger protein 11b (KOX 2) LOC283029 10q11.21 similar to Ras suppressor protein 1 BMS1L 10q11.21 BMS1-like, ribosome assembly protein (yeast) RET 10q11.2 ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease) GALNACT-2 10q11.21 chondroitin sulfate GalNAcT-2 LOC221002 FXYD4 10q11.21 FXYD domain containing ion transport regulator 4 HNRPF 10q11.21-q11.22 heterogeneous nuclear ribonucleoprotein F LOC283031 10q11.21 hypothetical protein LOC283031 ZNF239 10q11.22-q11.23 zinc finger protein 239 LOC387660 10 hypothetical gene supported by M98474 LOC220992 10q11.21 Zinc finger protein 93 (Zinc finger protein HTF34) ZNF32 10q23-q24 zinc finger protein 32 (KOX 30) HNRPA3 10p11.1 heterogeneous nuclear ribonucleoprotein A3 LOC283034 10q11.21 hypothetical LOC283034 CXCL12 10q11.2 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1) LOC387661 10 similar to ribosomal protein L9; 60S ribosomal protein L9 LOC387662 10 hypothetical gene supported by BX538120 RASSF4 10q11.21 Ras association (RalGDS/AF-6) domain family 4 C10orf10 10q11.21 chromosome 10 open reading frame 10 C10orf25 10q11.21 chromosome 10 open reading frame 25 ZNF22 10q11.2 zinc finger protein 22 (KOX 15) LOC340765 10q11.21 similar to double homeobox, 4; double homeobox protein 4
    RNA
    TRANSCRIPTS type messenger
    text alternatively spliced at its 3 prime end to produce multiple protein isoforms (PMID: 22875993)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    20 splicing 5629 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 RET51FKBP4 complex in adult neurons of the central nervous system
  • 19 splicing 4174 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
  • - splicing 3674 - 818 - 2010 20442138
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineadrenal gland   highly
    Nervousgangliaautonomic ganglia  highly
     gangliasensory gangliadorsal root highly
    Reproductivefemale systembreastmammary gland highly
    Visualeyeretinafovea  
     eyeretinamacula  
     eyeuveachoroid  
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    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
  • 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
  • SystemTypeDisorderPubmed
    cancer  
    small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations including RET and have shown efficacy against a variety of malignancies
    cancerreproductivebreast
    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