UniProt functional annotation for P07949



	UniProt functional annotation for P07949

UniProt code: P07949.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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 (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK- signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099). {ECO:0000269|PubMed:20064382, ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};

Activity 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. {ECO:0000269|PubMed:17664273, ECO:0000269|PubMed:17884497, ECO:0000269|PubMed:19053769, ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:20409618, ECO:0000269|PubMed:20605972, ECO:0000269|PubMed:21134556}.

Subunit: 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) (PubMed:21454698). Extracellular cell- membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (PubMed:21357690). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (PubMed:19366855). 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 (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with GFRAL requires previous GDF15-binding to GFRAL (PubMed:28846097, PubMed:28846099). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GDNF (PubMed:21994944). {ECO:0000250|UniProtKB:P35546, ECO:0000269|PubMed:18753381, ECO:0000269|PubMed:19366855, ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:28953886}; 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. In the presence of SORL1 and GFRA1, directed to endosomes. {ECO:0000269|PubMed:23333276}.

Induction: Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3. {ECO:0000269|PubMed:19853745}.

Ptm: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr- 1062. {ECO:0000269|PubMed:11061555, ECO:0000269|PubMed:14711813, ECO:0000269|PubMed:16778204, ECO:0000269|PubMed:16928683, ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:28846099}.

Ptm: 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. {ECO:0000269|PubMed:21357690}.

Polymorphism: The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.

Disease: Colorectal cancer (CRC) [MIM:114500]: 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 variants affecting the gene represented in this entry.

Disease: Hirschsprung disease 1 (HSCR1) [MIM:142623]: 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. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.62}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Medullary thyroid carcinoma (MTC) [MIM:155240]: 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. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Multiple neoplasia 2B (MEN2B) [MIM:162300]: 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. {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866, ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615, ECO:0000269|PubMed:9360560}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Pheochromocytoma (PCC) [MIM:171300]: 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. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). 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 (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269|PubMed:10439047, ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916, ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021, ECO:0000269|PubMed:3037315}.

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) [MIM:209880]: 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. {ECO:0000269|PubMed:12086152, ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:9497256}. Note=The disease is caused by variants affecting the gene represented in this entry.

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

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Sequence caution: Sequence=AAA36524.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=AAA36786.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA33787.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAC14882.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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 (PubMed:28846097, PubMed:28953886, PubMed:28846099). Isoform 1 in complex with GFRAL induces higher activation of MAPK- signaling pathway than isoform 2 in complex with GFRAL (PubMed:28846099). {ECO:0000269\|PubMed:20064382, ECO:0000269\|PubMed:20616503, ECO:0000269\|PubMed:20702524, ECO:0000269\|PubMed:21357690, ECO:0000269\|PubMed:21454698, ECO:0000269\|PubMed:28846097, ECO:0000269\|PubMed:28846099, ECO:0000269\|PubMed:28953886}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028};
Activity 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. {ECO:0000269\|PubMed:17664273, ECO:0000269\|PubMed:17884497, ECO:0000269\|PubMed:19053769, ECO:0000269\|PubMed:20117004, ECO:0000269\|PubMed:20409618, ECO:0000269\|PubMed:20605972, ECO:0000269\|PubMed:21134556}.
Subunit:		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) (PubMed:21454698). Extracellular cell- membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (PubMed:21357690). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (PubMed:19366855). 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 (PubMed:28953886, PubMed:28846097, PubMed:28846099). Interaction with GFRAL requires previous GDF15-binding to GFRAL (PubMed:28846097, PubMed:28846099). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GDNF (PubMed:21994944). {ECO:0000250\|UniProtKB:P35546, ECO:0000269\|PubMed:18753381, ECO:0000269\|PubMed:19366855, ECO:0000269\|PubMed:21357690, ECO:0000269\|PubMed:21454698, ECO:0000269\|PubMed:21994944, ECO:0000269\|PubMed:23333276, ECO:0000269\|PubMed:28846097, ECO:0000269\|PubMed:28846099, ECO:0000269\|PubMed:28953886}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:19823924, ECO:0000269\|PubMed:21994944, ECO:0000269\|PubMed:23333276, ECO:0000269\|PubMed:28953886}; 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. In the presence of SORL1 and GFRA1, directed to endosomes. {ECO:0000269\|PubMed:23333276}.
Induction:		Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3. {ECO:0000269\|PubMed:19853745}.
Ptm:		Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr- 1062. {ECO:0000269\|PubMed:11061555, ECO:0000269\|PubMed:14711813, ECO:0000269\|PubMed:16778204, ECO:0000269\|PubMed:16928683, ECO:0000269\|PubMed:20117004, ECO:0000269\|PubMed:28846099}.
Ptm:		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. {ECO:0000269\|PubMed:21357690}.
Polymorphism:		The Cys-982 polymorphism may be associated with an increased risk for developing Hirschsprung disease.
Disease:		Colorectal cancer (CRC) [MIM:114500]: 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 variants affecting the gene represented in this entry.
Disease:		Hirschsprung disease 1 (HSCR1) [MIM:142623]: 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. {ECO:0000269\|PubMed:10090908, ECO:0000269\|PubMed:10484767, ECO:0000269\|PubMed:10618407, ECO:0000269\|PubMed:22174939, ECO:0000269\|PubMed:7581377, ECO:0000269\|PubMed:7633441, ECO:0000269\|PubMed:7704557, ECO:0000269\|PubMed:7881414, ECO:0000269\|PubMed:8114938, ECO:0000269\|PubMed:8114939, ECO:0000269\|PubMed:9043870, ECO:0000269\|PubMed:9090527, ECO:0000269\|PubMed:9094028, ECO:0000269\|PubMed:9259198, ECO:0000269\|PubMed:9384613, ECO:0000269\|Ref.62}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Medullary thyroid carcinoma (MTC) [MIM:155240]: 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. {ECO:0000269\|PubMed:10323403, ECO:0000269\|PubMed:10826520, ECO:0000269\|PubMed:11692159, ECO:0000269\|PubMed:7784092, ECO:0000269\|PubMed:7845675, ECO:0000269\|PubMed:7849720, ECO:0000269\|PubMed:7874109, ECO:0000269\|PubMed:7881414, ECO:0000269\|PubMed:7915165, ECO:0000269\|PubMed:8103403, ECO:0000269\|PubMed:8557249, ECO:0000269\|PubMed:8625130, ECO:0000269\|PubMed:8807338, ECO:0000269\|PubMed:9223675, ECO:0000269\|PubMed:9259198, ECO:0000269\|PubMed:9398735, ECO:0000269\|PubMed:9452077, ECO:0000269\|PubMed:9506724, ECO:0000269\|PubMed:9621513, ECO:0000269\|PubMed:9677065}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Multiple neoplasia 2B (MEN2B) [MIM:162300]: 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. {ECO:0000269\|PubMed:7906417, ECO:0000269\|PubMed:7906866, ECO:0000269\|PubMed:7911697, ECO:0000269\|PubMed:8595427, ECO:0000269\|PubMed:8807338, ECO:0000269\|PubMed:9294615, ECO:0000269\|PubMed:9360560}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Pheochromocytoma (PCC) [MIM:171300]: 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. {ECO:0000269\|PubMed:12000816}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269\|PubMed:10522989, ECO:0000269\|PubMed:7860065, ECO:0000269\|PubMed:7874109, ECO:0000269\|PubMed:7881414, ECO:0000269\|PubMed:7915165, ECO:0000269\|PubMed:8099202, ECO:0000269\|PubMed:8103403, ECO:0000269\|PubMed:8626834, ECO:0000269\|PubMed:8807338, ECO:0000269\|PubMed:9097963, ECO:0000269\|PubMed:9384613, ECO:0000269\|PubMed:9452064}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Note=Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs) (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene (PubMed:2406025). 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 (PubMed:2734021). Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916). Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047). Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269\|PubMed:10439047, ECO:0000269\|PubMed:10980597, ECO:0000269\|PubMed:12787916, ECO:0000269\|PubMed:2406025, ECO:0000269\|PubMed:2734021, ECO:0000269\|PubMed:3037315}.
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) [MIM:209880]: 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. {ECO:0000269\|PubMed:12086152, ECO:0000269\|PubMed:14566559, ECO:0000269\|PubMed:9497256}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.
Sequence caution:		Sequence=AAA36524.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=AAA36786.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA33787.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAC14882.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};