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This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
RET mutations and the RET fusion RET-PTC lead to activation of this tyrosine kinase receptor and are associated with thyroid cancers. RET point mutations are the most common mutations identified in medullary thyroid cancer (MTC) with germline and somatic mutations in RET associated with hereditary and sporadic forms, respectively. The most common somatic form mutation is M918T (exon 16) and a variety of other mutations effecting exons 10, 11 and 15 have been described. The prognostic significance of these mutations have been hotly debated in the field, however, data suggests that some RET mutation may confer drug resistence. No RET-specific agents are currently clinically available but several promiscuous kinase inhibitors that target RET, among others, have been approved for MTC treatment.
RET (Ret Proto-Oncogene) is a Protein Coding gene. Diseases associated with RET include Multiple Endocrine Neoplasia, Type Iia and Thyroid Carcinoma, Familial Medullary. Among its related pathways are Neuroscience and GDNF-Family Ligands and Receptor Interactions. Gene Ontology (GO) annotations related to this gene include calcium ion binding and protein kinase activity. An important paralog of this gene is FLT4.
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000166 | nucleotide binding | IEA | -- |
GO:0004672 | protein kinase activity | IEA | -- |
GO:0004713 | protein tyrosine kinase activity | TAS | 7824936 |
GO:0004714 | transmembrane receptor protein tyrosine kinase activity | TAS | -- |
GO:0005509 | calcium ion binding | IEA,IDA | 11445581 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0005768 | endosome | IEA | -- |
GO:0005769 | early endosome | IEA | -- |
GO:0005886 | plasma membrane | TAS | -- |
GO:0005887 | integral component of plasma membrane | IBA,IDA | 19823924 |
GO:0010008 | endosome membrane | IEA,IDA | 19823924 |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | RET signaling |
.92
|
.92
|
2 | Developmental Biology |
.51
|
|
3 | Cytokine Signaling in Immune system | ||
4 | Innate Immune System |
.61
|
|
5 | Signaling by GPCR |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000165 | MAPK cascade | TAS | -- |
GO:0000187 | activation of MAPK activity | IMP | 28953886 |
GO:0001657 | ureteric bud development | IEA | -- |
GO:0001755 | neural crest cell migration | IEA | -- |
GO:0001838 | embryonic epithelial tube formation | IEA | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
cabozantinib | Approved, Investigational | Pharma | Target, antagonist, inhibitor | Kinase Inhibitors, Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors | 0 | |
Vandetanib | Approved | Pharma | Target, inhibitor, Biomarker | VEGFR, EGFR, and RET inhibitor, EGFR Inhibitors, Kinase Inhibitors, Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors | 0 | |
regorafenib | Approved | Pharma | Target, inhibitor | Inhibitor of VEGFR/PDGFR/FGFR/mutant kit/RET/Raf-1, Kinase Inhibitors, Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors | 0 | |
imatinib | Approved | Pharma | Target, inhibitor | Kinase Inhibitors, SRC/BCR-ABL tyrosine kinase inhibitors | 0 | |
Sorafenib | Approved, Investigational | Pharma | Target, inhibitor, inhibitors | Raf kinases and tyrosine kinases inhibitor, RAF, VEGFR2, and PDGFR-beta inhibitors, Kinase Inhibitors, Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors | 779 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs | |
---|---|---|---|---|---|---|
ADP |
|
Agonist, Full agonist, Partial agonist, Gating inhibitor, Antagonist | 58-64-0 |
|
Compound | Action | Cas Number |
---|---|---|
Amuvatinib (MP-470, HPK 56) | Tyrosine kinase inhibitor | 850879-09-3 |
Apatinib | VEGFR2 inhibitor, orally bioavailable, selective | 811803-05-1 |
AST 487 | RET kinase inhibitor | 630124-46-8 |
Cabozantinib (XL184, BMS-907351) | VEGFR2/Met/Ret/Kit/FLT//AXL inhibitor | 849217-68-1 |
Danusertib (PHA-739358) | Pan-aurora kinase inhibitor | 827318-97-8 |
Motesanib Diphosphate (AMG-706) | VEGFR/ PDGFR/c-Kit/Ret inhibitor | 857876-30-3 |
Regorafenib | Inhibitor of VEGFR/PDGFR/FGFR/mutant kit/RET/Raf-1 | 755037-03-7 |
Regorafenib hydrochloride | 835621-07-3 | |
Regorafenib monohydrate | Tyrosine kinase inhibitor | 1019206-88-2 |
SU5416 | VEGF receptor inhibitor and AHR agonist | 204005-46-9 |
Sunitinib malate | VEGFR/PDGFRβ/ KIT/ FLT3/RET/CSF-1R inhibitor | 341031-54-7 |
TG101209 | JAK2/3 inhibitor | 936091-14-4 |
ExUns: | 1 | ^ | 2a | · | 2b | ^ | 3 | ^ | 4 | ^ | 5 | ^ | 6 | ^ | 7a | · | 7b | ^ | 8 | ^ | 9 | ^ | 10 | ^ | 11a | · | 11b | ^ | 12 | ^ | 13 | ^ | 14a | · | 14b | ^ | 15 | ^ | 16 | ^ | 17 | ^ | 18 | ^ | 19a | · | 19b | ^ | 20 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | ||||||||||||||||||||||||||||||||||||||||||||||||
SP2: | |||||||||||||||||||||||||||||||||||||||||||||||||
SP3: | - | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||
SP4: | - | - | - | - | - | - | - | - |
This gene was present in the common ancestor of animals.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | RET 30 31 |
|
OneToOne | |
Cow (Bos Taurus) |
Mammalia | RET 30 31 |
|
OneToOne | |
Dog (Canis familiaris) |
Mammalia | RET 30 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Ret 30 |
|
||
Mouse (Mus musculus) |
Mammalia | Ret 30 17 31 |
|
OneToOne | |
Oppossum (Monodelphis domestica) |
Mammalia | RET 31 |
|
OneToOne | |
Platypus (Ornithorhynchus anatinus) |
Mammalia | RET 31 |
|
OneToOne | |
Chicken (Gallus gallus) |
Aves | RET 30 31 |
|
OneToOne | |
Lizard (Anolis carolinensis) |
Reptilia | RET 31 |
|
OneToOne | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | ret 30 |
|
||
African clawed frog (Xenopus laevis) |
Amphibia | ret-A 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | ret 30 31 |
|
OneToOne | |
ret1 30 |
|
||||
Fruit Fly (Drosophila melanogaster) |
Insecta | tor 32 |
|
|
|
Ret 31 32 |
|
OneToOne | |||
Worm (Caenorhabditis elegans) |
Secernentea | R151.4 32 |
|
|
|
C24G6.2a 32 |
|
|
|||
C24G6.2b 32 |
|
|
|||
kin-9 32 |
|
|
|||
Y50D4B.6 32 |
|
|
|||
F09A5.2 32 |
|
|
|||
kin-16 32 |
|
|
|||
ver-4 32 |
|
|
|||
Y38H6C.20 32 |
|
|
|||
W01B6.5 32 |
|
|
|||
F59A3.8 32 |
|
|
|||
R09D1.12 32 |
|
|
|||
F09G2.1 32 |
|
|
SNP ID | Clinical significance and condition | Chr 10 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
477312 | Uncertain Significance: Multiple endocrine neoplasia, type 2 | 43,111,238(+) | CA/TG | MISSENSE_VARIANT | |
639162 | Uncertain Significance: Multiple endocrine neoplasia, type 2 | 43,116,698(+) | G/A | MISSENSE_VARIANT | |
639960 | Uncertain Significance: Multiple endocrine neoplasia, type 2 | 43,111,237(+) | G/A | MISSENSE_VARIANT | |
640429 | Uncertain Significance: Multiple endocrine neoplasia, type 2 | 43,102,427(+) | C/G | SYNONYMOUS_VARIANT | |
640598 | Uncertain Significance: Multiple endocrine neoplasia, type 2 | 43,109,201(+) | G/A | MISSENSE_VARIANT |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
dgv723n100 | CNV | gain | 25217958 |
dgv724n100 | CNV | gain | 25217958 |
dgv725n100 | CNV | gain | 25217958 |
dgv726n100 | CNV | gain | 25217958 |
dgv727n100 | CNV | gain | 25217958 |
esv275022 | CNV | gain+loss | 21479260 |
nsv1038102 | CNV | gain | 25217958 |
nsv1042310 | CNV | loss | 25217958 |
nsv1052276 | CNV | gain | 25217958 |
nsv1143500 | CNV | deletion | 24896259 |
nsv1161940 | CNV | duplication | 26073780 |
nsv522566 | CNV | loss | 19592680 |
nsv522592 | CNV | loss | 19592680 |
nsv550695 | CNV | gain | 21841781 |
nsv825350 | CNV | gain | 20364138 |
nsv951564 | CNV | deletion | 24416366 |