Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Proto-oncogene tyrosine-protein kinase receptor Ret

Gene

Ret

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways (By similarity).By similarity

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei759ATPPROSITE-ProRule annotation1
Active sitei875Proton acceptorPROSITE-ProRule annotation1
Binding sitei893InhibitorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi731 – 739ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processCell adhesion
LigandATP-binding, Calcium, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-RNO-5673001 RAF/MAP kinase cascade
R-RNO-8853659 RET signaling

Names & Taxonomyi

Protein namesi
Recommended name:
Proto-oncogene tyrosine-protein kinase receptor Ret (EC:2.7.10.1)
Cleaved into the following 2 chains:
Gene namesi
Name:Ret
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 4

Organism-specific databases

RGDi3556 Ret

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini24 – 637ExtracellularSequence analysisAdd BLAST614
Transmembranei638 – 658HelicalSequence analysisAdd BLAST21
Topological domaini659 – 1115CytoplasmicSequence analysisAdd BLAST457

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 23Sequence analysisAdd BLAST23
ChainiPRO_000042487424 – 1115Proto-oncogene tyrosine-protein kinase receptor RetAdd BLAST1092
ChainiPRO_000042487529 – 708Extracellular cell-membrane anchored RET cadherin 120 kDa fragmentBy similarityAdd BLAST680
ChainiPRO_0000424876709 – 1018Soluble RET kinase fragmentBy similarityAdd BLAST310

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi98N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi137 ↔ 142By similarity
Glycosylationi151N-linked (GlcNAc...) asparagineBy similarity1
Glycosylationi156N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi199N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi378N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi395N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi449N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi469N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi555N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei697PhosphoserineBy similarity1
Modified residuei807Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei810Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei901Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei906Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei982Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1016Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1063Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1091Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei1097Phosphotyrosine; by autocatalysisBy similarity1

Post-translational modificationi

Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-906, Tyr-1016 and Tyr-1063 (By similarity).By similarity
Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei708 – 709Cleavage; by caspase-3By similarity2
Sitei1018 – 1019Cleavage; by caspase-3By similarity2

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiG3V9H8
PRIDEiG3V9H8

PTM databases

iPTMnetiG3V9H8
PhosphoSitePlusiG3V9H8

Expressioni

Tissue specificityi

Expressed in neurons and kidney glomeruli podocytes (at protein level) (PubMed:18753381). Detected at least in colon, duodenum, adipose tissue, heart, jejenum, lung, muscle, spleen, stomac, testis and thymus (PubMed:28846099).2 Publications

Gene expression databases

BgeeiENSRNOG00000014751 Expressed in 9 organ(s), highest expression level in skeletal muscle tissue
GenevisibleiG3V9H8 RN

Interactioni

Subunit structurei

Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5 (By similarity). The phosphorylated form interacts with PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain) (By similarity). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (By similarity). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (By similarity). Binds to ARTN (By similarity). Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction (PubMed:18753381). Interacts (via the extracellular domain) with GFRAL (via the extracellular domain); the interaction mediates cellular signaling upon interaction of GFRAL with its ligand GDF15. Interaction with GFRAL requires previous GDF15-binding to GFRAL (By similarity).By similarity1 Publication

Protein-protein interaction databases

BioGridi246844, 4 interactors
STRINGi10116.ENSRNOP00000047793

Structurei

3D structure databases

SMRiG3V9H8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini168 – 273CadherinPROSITE-ProRule annotationAdd BLAST106
Domaini725 – 1017Protein kinasePROSITE-ProRule annotationAdd BLAST293

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni806 – 808Inhibitors bindingBy similarity3

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118923
HOGENOMiHOG000010301
HOVERGENiHBG002609
InParanoidiG3V9H8
KOiK05126
OMAiNAHKPPI
OrthoDBiEOG091G0CQZ
PhylomeDBiG3V9H8
TreeFamiTF317640

Family and domain databases

InterProiView protein in InterPro
IPR002126 Cadherin-like_dom
IPR015919 Cadherin-like_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016249 Tyr_kinase_Ret_rcpt
PfamiView protein in Pfam
PF00028 Cadherin, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF000631 TyrPK_receptor_Ret, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00219 TyrKc, 1 hit
SUPFAMiSSF49313 SSF49313, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50268 CADHERIN_2, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform 1 (identifier: G3V9H8-1) [UniParc]FASTAAdd to basket
Also known as: Ret51

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MAKARSGAAG LGLKLFLLLP LLGEAPLGLY FSRDAYWERL YVDQPAGTPL
60 70 80 90 100
LYVHALRDAP GEVPSFRLGQ YLYGVYRTRL HENDWIHIDS GTGLLYLNQS
110 120 130 140 150
LDHSSWEQLS IRNGGFPLLT VFLQVFLGST AQREGECHWP GCARVYFSFI
160 170 180 190 200
NDTFPNCSSF KARDLCTPET GVSFRIRENR PPGTFYQFRM LPVQFLCPNI
210 220 230 240 250
SVKYKLLEGD GLPFRCDPDC LEVSTRWALD RELQEKYVLE AECAVAGPGA
260 270 280 290 300
NKEKVAVSFP VTVYDEDDSP PTFSGGVGTA SAVVEFKRKE GTVVATLQVF
310 320 330 340 350
DADVVPASGE LVRRYTSTLL SGDSWAQQTF RVEHTPNETL VQSNNNSVRA
360 370 380 390 400
TMHNYKLVLN RSLSISESRV LQLVVLVNDS DFQGPGSGVL FLHFNVSVLP
410 420 430 440 450
VTLNLPMAYS FPVNRRARRY AQIGKVCVEN CQEFSGVSIQ YKLQPSSTNC
460 470 480 490 500
SALGVVTSTE DTSGTLYVND TEALRRPECT ELQYTVVATD RQTRRQTQAS
510 520 530 540 550
LVVTVEGTYI AEEVGCPKSC AVNKRRPECE ECGGLGSPTG RCEWRQGDGK
560 570 580 590 600
GITRNFSTCS PSTRTCPDGH CDALESRDIN ICPQDCLRGP IVGGHERGER
610 620 630 640 650
QGIKAGYGIC NCFPDEKKCF CEPEDSQGPL CDELCRTVIT AAVLFSFIIS
660 670 680 690 700
VLLSTFCIHR YHKHAHKPPI ASAEMTFCRP AQGFPISYSS SGTRRPSLDS
710 720 730 740 750
MENQVSVDSF KIPEDPKWEF PRKNLVLGKT LGEGEFGKVV KATAFRLKGR
760 770 780 790 800
AGYTTVAVKM LKENASQSEL RDLLSEFNLL KQVNHPHVIK LYGACSQDGP
810 820 830 840 850
LLLIVEYAKY GSLRGFLRDS RKIGPAYVSS GGSRNSSSLD HPDERVLTMG
860 870 880 890 900
DLISFAWQIS RGMQYLAEMK LVHRDLAARN ILVAEGRKMK ISDFGLSRDV
910 920 930 940 950
YEEDSYVKKS KGRIPVKWMA IESLFDHIYT TQSDVWSFGV LLWEIVTLGG
960 970 980 990 1000
NPYPGIPPER LFNLLKTGHR MERPDNCSEE MYRLMLQCWK QEPDKRPVFA
1010 1020 1030 1040 1050
DISKDLEKMM VKSRDYLDLA ASTPSDSLLY DDGLSEEETP LVDCNSAPLP
1060 1070 1080 1090 1100
RSLPSTWIEN KLYGMSDPNW PGESPVPLTR ADGTSTGFPR YANDSVYANW
1110
MVSPSAAKLM DTFDS
Length:1,115
Mass (Da):124,237
Last modified:November 16, 2011 - v1
Checksum:iBF6EE55077F10F35
GO
Isoform 2 (identifier: G3V9H8-2) [UniParc]FASTAAdd to basket
Also known as: Ret9

The sequence of this isoform differs from the canonical sequence as follows:
     922-928: ESLFDHI → NSLSDHF
     1065-1073: MSDPNWPGE → RISHAFTRF
     1074-1115: Missing.

Show »
Length:1,073
Mass (Da):119,791
Checksum:i51E9316F9B3DFB0D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti30Y → C in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti30Y → C in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti90S → A in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti90S → A in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti264Y → YD in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti264Y → YD in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti356K → R in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti356K → R in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti389V → F in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti389V → F in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti552I → T in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti552I → T in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti628G → A in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti628G → A in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti749G → D in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti749G → D in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti917K → N in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti917K → N in CAC10583 (PubMed:11328649).Curated1
Sequence conflicti975D → N in CAC10568 (PubMed:11328649).Curated1
Sequence conflicti975D → N in CAC10583 (PubMed:11328649).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_053545922 – 928ESLFDHI → NSLSDHF in isoform 2. 1 Publication7
Alternative sequenceiVSP_0535461065 – 1073MSDPNWPGE → RISHAFTRF in isoform 2. 1 Publication9
Alternative sequenceiVSP_0535471074 – 1115Missing in isoform 2. 1 PublicationAdd BLAST42

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ299016 mRNA Translation: CAC10568.1
AJ299017 mRNA Translation: CAC10569.1
AJ298999
, AJ299000, AJ299001, AJ299002, AJ299003, AJ299004, AJ299005, AJ299006, AJ299007, AJ299008, AJ299009, AJ299010, AJ299011, AJ299012, AJ299013, AJ299014 Genomic DNA Translation: CAC10584.1
AJ298999
, AJ299000, AJ299001, AJ299002, AJ299003, AJ299004, AJ299005, AJ299006, AJ299007, AJ299008, AJ299009, AJ299010, AJ299011, AJ299012, AJ299013, AJ299014, AJ299015 Genomic DNA Translation: CAC10583.1
AABR06033186 Genomic DNA No translation available.
CH473964 Genomic DNA Translation: EDM02082.1
CH473964 Genomic DNA Translation: EDM02083.1
RefSeqiNP_036775.2, NM_012643.2 [G3V9H8-1]
XP_017447959.1, XM_017592470.1 [G3V9H8-1]
UniGeneiRn.93200

Genome annotation databases

EnsembliENSRNOT00000047685; ENSRNOP00000047793; ENSRNOG00000014751 [G3V9H8-1]
GeneIDi24716
KEGGirno:24716

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ299016 mRNA Translation: CAC10568.1
AJ299017 mRNA Translation: CAC10569.1
AJ298999
, AJ299000, AJ299001, AJ299002, AJ299003, AJ299004, AJ299005, AJ299006, AJ299007, AJ299008, AJ299009, AJ299010, AJ299011, AJ299012, AJ299013, AJ299014 Genomic DNA Translation: CAC10584.1
AJ298999
, AJ299000, AJ299001, AJ299002, AJ299003, AJ299004, AJ299005, AJ299006, AJ299007, AJ299008, AJ299009, AJ299010, AJ299011, AJ299012, AJ299013, AJ299014, AJ299015 Genomic DNA Translation: CAC10583.1
AABR06033186 Genomic DNA No translation available.
CH473964 Genomic DNA Translation: EDM02082.1
CH473964 Genomic DNA Translation: EDM02083.1
RefSeqiNP_036775.2, NM_012643.2 [G3V9H8-1]
XP_017447959.1, XM_017592470.1 [G3V9H8-1]
UniGeneiRn.93200

3D structure databases

SMRiG3V9H8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi246844, 4 interactors
STRINGi10116.ENSRNOP00000047793

PTM databases

iPTMnetiG3V9H8
PhosphoSitePlusiG3V9H8

Proteomic databases

PaxDbiG3V9H8
PRIDEiG3V9H8

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000047685; ENSRNOP00000047793; ENSRNOG00000014751 [G3V9H8-1]
GeneIDi24716
KEGGirno:24716

Organism-specific databases

CTDi5979
RGDi3556 Ret

Phylogenomic databases

eggNOGiKOG0200 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118923
HOGENOMiHOG000010301
HOVERGENiHBG002609
InParanoidiG3V9H8
KOiK05126
OMAiNAHKPPI
OrthoDBiEOG091G0CQZ
PhylomeDBiG3V9H8
TreeFamiTF317640

Enzyme and pathway databases

ReactomeiR-RNO-5673001 RAF/MAP kinase cascade
R-RNO-8853659 RET signaling

Miscellaneous databases

PROiPR:G3V9H8

Gene expression databases

BgeeiENSRNOG00000014751 Expressed in 9 organ(s), highest expression level in skeletal muscle tissue
GenevisibleiG3V9H8 RN

Family and domain databases

InterProiView protein in InterPro
IPR002126 Cadherin-like_dom
IPR015919 Cadherin-like_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016249 Tyr_kinase_Ret_rcpt
PfamiView protein in Pfam
PF00028 Cadherin, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PIRSFiPIRSF000631 TyrPK_receptor_Ret, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00219 TyrKc, 1 hit
SUPFAMiSSF49313 SSF49313, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50268 CADHERIN_2, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiRET_RAT
AccessioniPrimary (citable) accession number: G3V9H8
Secondary accession number(s): Q9EPA1, Q9EPC3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 22, 2014
Last sequence update: November 16, 2011
Last modified: November 7, 2018
This is version 59 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again