RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret

RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret » C-ret;
Hydrophobic Thickness 42.8 ± 2.6 Å
Tilt Angle 0 ± 1°
ΔGtransfer -47.4 kcal/mol
ΔGfold -20.1 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 633-660 (631-664)
Pathways

Endocytosis (KEGG)

Pathways in cancer (KEGG)

Thyroid cancer (KEGG)

PDB 4ux8 (A/B=29-635), 2ivs (A/B=705-1013), 2x2m (A/B=705-1013), 2x2u (A=29-270), 2ivt (A=705-1013), 2ivu (A=705-1013), 2ivv (A=705-1013), 2x2k (A=705-1013), 2x2l (A=705-1013), 4cki (A=705-1013), 4ckj (A=705-1013)
OPM none
Complexes

RET:RET_HUMAN

Interactions

EGFR, Complex: EGFR:RET, PubMed

GOGA5, Complex: RET:GOGA5, PubMed

NOTC3, Complex: RET:NOTC3

PTPRF, Complex: RET:PTPRF, PubMed

RET, Complex: Homodimer of proto-oncogene tyrosine-protein kinase receptor RET, PDBID: 2IVS

Domains

AA: 172-262, PDBID: 2X2U, Subunit A, Seq Identity:100%, Cadherin domain

AA: 724-1005, PDBID: 2IVS, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret
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.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3- thienyl) nicotinonitrile analogs, 3- and 4-substituted beta- carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), sunitinib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.

SUBUNIT: Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7. Interacts (not phosphorylated) with CC PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex. Binds to ARTN. Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction.

INDUCTION: Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.

DISEASE: Colorectal cancer (CRC) OMIM: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry.

DISEASE: Hirschsprung disease 1 (HSCR1) OMIM: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. is caused by mutations affecting the gene represented in this entry.

DISEASE: Medullary thyroid carcinoma (MTC) OMIM: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. mutations affecting the gene represented in this entry.

DISEASE: Multiple neoplasia 2B (MEN2B) OMIM: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Pheochromocytoma (PCC) OMIM: A catecholamine- producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. associated with variations affecting the gene represented in this entry.

DISEASE: Multiple neoplasia 2A (MEN2A) OMIM: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. mutations affecting the gene represented in this entry.

DISEASE: Thyroid papillary carcinoma (TPC) OMIM: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene; translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes.

DISEASE: Note=Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.

DISEASE: Congenital central hypoventilation syndrome (CCHS) OMIM: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. mutations affecting the gene represented in this entry.

MISCELLANEOUS: Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).

UniProt features for RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret
SIGNAL 1 28 Potential.
CHAIN 29 1114 Proto-oncogene tyrosine-protein kinase receptor Ret.
CHAIN 29 707 Extracellular cell-membrane anchored RET cadherin 120 kDa fragment.
CHAIN 708 1017 Soluble RET kinase fragment.
DOMAIN 168 272 Cadherin.
DOMAIN 724 1016 Protein kinase.
REGION 805 807 Inhibitors binding.
ACT_SITE 874 874 Proton acceptor (By similarity).
SITE 587 588 Breakpoint for translocation to form the TRIM27/RET oncogene.
SITE 707 708 Cleavage; by caspase-3.
SITE 712 713 Breakpoint for translocation to form PCM1-RET; RET-CCDC6; RET-GOLGA5; RET- TRIM24 and RET-TRIM33 oncogenes.
SITE 1017 1018 Cleavage; by caspase-3.
DISULFID 137 142
Amino Acid Sequence for RET_HUMAN » Proto-oncogene tyrosine-protein kinase receptor Ret
MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL LYVHALRDAP EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVYFSFF NTSFPACSSL KPRELCFPET RPSFRIRENR PPGTFHQFRL LPVQFLCPNI SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV AVCTVHAGAR EEVVMVPFPV TVYDEDDSAP TFPAGVDTAS AVVEFKRKED TVVATLRVFD ADVVPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA QIGKVCVENC QAFSGINVQY KLHSSGANCS TLGVVTSAED TSGILFVNDT KALRRPKCAE LHYMVVATDQ QTSRQAQAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR CEWRQGDGKG ITRNFSTCSP STKTCPDGHC DVVETQDINI CPQDCLRGSI VGGHEPGEPR GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA AVLFSFIVSV LLSAFCIHCY HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GEGEFGKVVK ATAFHLKGRA GYTTVAVKML KENASPSELR DLLSEFNVLK QVNHPHVIKL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH PDERALTMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY EEDSYVKRSQ GRIPVKWMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGIPPERL FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFAD ISKDLEKMMV KRRDYLDLAA STPSDSLIYD DGLSEEETPL VDCNNAPLPR ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGFPRY PNDSVYANWM LSPSAAKLMD TFDS