Protein: Proto-oncogene tyrosine-protein kinase receptor Ret (EC 2.7.10.1) (Cadherin family member 12) (Proto-oncogene c-Ret) [Cleaved into: Soluble RET kinase fragment; Extracellular cell-membrane anchored RET cadherin 120 kDa fragment] (P07949)
Organism: Homo sapiens (Human)
Function: 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. 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. Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL.
Subcellular location: Cell membrane {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:9575150}; Single-pass type I membrane protein {ECO:0000269|PubMed:19823924}. Endosome membrane {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:23333276}; Single-pass type I membrane protein {ECO:0000269|PubMed:19823924}. Note=Predominantly located on the plasma membrane (PubMed:23333276, PubMed:9575150). In the presence of SORL1 and GFRA1, directed to endosomes (PubMed:23333276). {ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:9575150}.
Sequence: MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAELHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [699-1005]
- IPR055162: RET, cysteine rich domain (domain) [518-620]
- IPR020635: Tyrosine-protein kinase, catalytic domain (domain) [724-1005]
- IPR050122: Receptor Tyrosine Kinase (family) [479-1011]
- IPR041317: RET, cadherin-like domain 4 (domain) [405-506]
- IPR002126: Cadherin-like (domain) [168-272]
- IPR041163: Ret, cadherin like domain 1 (domain) [29-153]
- IPR040667: Tyrosine-protein kinase receptor Ret, cadherin like domain 3 (domain) [265-379]
- IPR001245: Serine-threonine/tyrosine-protein kinase, catalytic domain (domain) [725-1005]
- IPR017441: Protein kinase, ATP binding site (binding_site) [730-758]
- IPR000719: Protein kinase domain (domain) [724-1016]
- IPR008266: Tyrosine-protein kinase, active site (active_site) [870-882]
- IPR015919: Cadherin-like superfamily (homologous_superfamily) [167-246]
- IPR016249: Tyrosine-protein kinase, Ret receptor (family) [3-1114]
Interaction partners: - GDNF family receptor alpha-2
- GDNF family receptor alpha-1
- Neurturin
- GDNF family receptor alpha-3
- Artemin
- Glial cell line-derived neurotrophic factor
- GDNF family receptor alpha-like
- Persephin
- Nuclear receptor coactivator 4
- Coiled-coil domain-containing protein 6
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0040011 (locomotion), GO:0048519 (negative regulation of biological process), GO:0009605 (response to external stimulus), GO:0048856 (anatomical structure development), GO:0009653 (anatomical structure morphogenesis), GO:0048870 (cell motility), GO:0042221 (response to chemical), GO:0042330 (taxis), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0051239 (regulation of multicellular organismal process), GO:0050793 (regulation of developmental process), GO:0065008 (regulation of biological quality), GO:0009719 (response to endogenous stimulus), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0048523 (negative regulation of cellular process), GO:0007165 (signal transduction), GO:0048869 (cellular developmental process), GO:0023056 (positive regulation of signaling), GO:0007275 (multicellular organism development), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0071704 (organic substance metabolic process), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0051094 (positive regulation of developmental process), GO:0007154 (cell communication), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0060548 (negative regulation of cell death), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0070848 (response to growth factor), GO:0009966 (regulation of signal transduction), GO:0071495 (cellular response to endogenous stimulus), GO:0060255 (regulation of macromolecule metabolic process), GO:0050803 (regulation of synapse structure or activity), GO:0001817 (regulation of cytokine production), GO:0044089 (positive regulation of cellular component biogenesis), GO:0044087 (regulation of cellular component biogenesis), GO:0006793 (phosphorus metabolic process), GO:0000902 (cell morphogenesis), GO:1904018 (positive regulation of vasculature development), GO:0022603 (regulation of anatomical structure morphogenesis), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0007166 (cell surface receptor signaling pathway), GO:0016043 (cellular component organization), GO:0051128 (regulation of cellular component organization), GO:0006935 (chemotaxis), GO:0016477 (cell migration), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0009967 (positive regulation of signal transduction), GO:0050790 (regulation of catalytic activity), GO:0044093 (positive regulation of molecular function), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0008285 (negative regulation of cell population proliferation), GO:0019538 (protein metabolic process), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:2000026 (regulation of multicellular organismal development), GO:0042127 (regulation of cell population proliferation), GO:0010941 (regulation of cell death), GO:0010646 (regulation of cell communication), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0010647 (positive regulation of cell communication), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0045834 (positive regulation of lipid metabolic process), GO:0043254 (regulation of protein-containing complex assembly), GO:0030030 (cell projection organization), GO:0050807 (regulation of synapse organization), GO:0051246 (regulation of protein metabolic process), GO:0043069 (negative regulation of programmed cell death), GO:0043067 (regulation of programmed cell death), GO:0010468 (regulation of gene expression), GO:0048666 (neuron development), GO:0043412 (macromolecule modification), GO:0007399 (nervous system development), GO:0001501 (skeletal system development), GO:1902533 (positive regulation of intracellular signal transduction), GO:0043085 (positive regulation of catalytic activity), GO:0045667 (regulation of osteoblast differentiation), GO:0010562 (positive regulation of phosphorus metabolic process), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:0010562 (positive regulation of phosphorus metabolic process), GO:1901888 (regulation of cell junction assembly), GO:1901342 (regulation of vasculature development), GO:0045766 (positive regulation of angiogenesis), GO:0006796 (phosphate-containing compound metabolic process), GO:0036211 (protein modification process), GO:0022008 (neurogenesis), GO:0036211 (protein modification process), GO:0022008 (neurogenesis), GO:0038179 (neurotrophin signaling pathway), GO:0051965 (positive regulation of synapse assembly), GO:0051247 (positive regulation of protein metabolic process), GO:0045765 (regulation of angiogenesis), GO:0051338 (regulation of transferase activity), GO:0030182 (neuron differentiation), GO:0071363 (cellular response to growth factor stimulus), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process), GO:0042981 (regulation of apoptotic process), GO:0045937 (positive regulation of phosphate metabolic process), GO:0120039 (plasma membrane bounded cell projection morphogenesis), GO:0051897 (positive regulation of protein kinase B signaling), GO:0018193 (peptidyl-amino acid modification), GO:0016310 (phosphorylation), GO:0043549 (regulation of kinase activity), GO:0051896 (regulation of protein kinase B signaling), GO:0007169 (transmembrane receptor protein tyrosine kinase signaling pathway), GO:0043410 (positive regulation of MAPK cascade), GO:0048699 (generation of neurons), GO:0031401 (positive regulation of protein modification process), GO:0043408 (regulation of MAPK cascade), GO:0051347 (positive regulation of transferase activity), GO:0031399 (regulation of protein modification process), GO:0043066 (negative regulation of apoptotic process), GO:0006468 (protein phosphorylation), GO:0120036 (plasma membrane bounded cell projection organization), GO:0019220 (regulation of phosphate metabolic process), GO:0031175 (neuron projection development), GO:0001932 (regulation of protein phosphorylation), GO:0070374 (positive regulation of ERK1 and ERK2 cascade), GO:0045859 (regulation of protein kinase activity), GO:0042327 (positive regulation of phosphorylation), GO:0043406 (positive regulation of MAP kinase activity), GO:0001934 (positive regulation of protein phosphorylation), GO:1904035 (regulation of epithelial cell apoptotic process), GO:0070372 (regulation of ERK1 and ERK2 cascade), GO:0018212 (peptidyl-tyrosine modification), GO:0042325 (regulation of phosphorylation), GO:0033674 (positive regulation of kinase activity), GO:0043550 (regulation of lipid kinase activity), GO:0046777 (protein autophosphorylation), GO:0071900 (regulation of protein serine/threonine kinase activity), GO:0042509 (regulation of tyrosine phosphorylation of STAT protein), GO:0050730 (regulation of peptidyl-tyrosine phosphorylation), GO:0050731 (positive regulation of peptidyl-tyrosine phosphorylation), GO:0045860 (positive regulation of protein kinase activity), GO:0043405 (regulation of MAP kinase activity), GO:0071902 (positive regulation of protein serine/threonine kinase activity)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0016020 (membrane), GO:0031974 (membrane-enclosed lumen), GO:0009986 (cell surface), GO:0071944 (cell periphery), GO:0005737 (cytoplasm), GO:0012505 (endomembrane system), GO:0005654 (nucleoplasm), GO:0031090 (organelle membrane), GO:0031410 (cytoplasmic vesicle), GO:0043229 (intracellular organelle), GO:0005768 (endosome), GO:0005794 (Golgi apparatus), GO:0043233 (organelle lumen), GO:0043227 (membrane-bounded organelle), GO:0005886 (plasma membrane), GO:0043231 (intracellular membrane-bounded organelle), GO:0098588 (bounding membrane of organelle), GO:0012506 (vesicle membrane), GO:0005769 (early endosome), GO:0010008 (endosome membrane), GO:0031982 (vesicle), GO:0070013 (intracellular organelle lumen), GO:0030659 (cytoplasmic vesicle membrane), GO:0097708 (intracellular vesicle), GO:0005634 (nucleus), GO:0031901 (early endosome membrane), GO:0031981 (nuclear lumen)