RET proto-oncogene

Last updated
RET
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RET , Ret, PTC, RET51, RET9, c-Ret, CDHF12, CDHR16, HSCR1, MEN2A, MEN2B, MTC1, RET-ELE1, ret proto-oncogene
External IDs OMIM: 164761 MGI: 97902 HomoloGene: 7517 GeneCards: RET
Orthologs
SpeciesHumanMouse
Entrez

5979

19713

Ensembl

ENSG00000165731

ENSMUSG00000030110

UniProt

P07949

P35546

RefSeq (mRNA)

NM_000323
NM_020629
NM_020630
NM_020975
NM_001355216

NM_001080780
NM_009050

RefSeq (protein)

NP_065681
NP_066124
NP_001342145
NP_066124.1

NP_001074249
NP_033076

Location (UCSC) Chr 10: 43.08 – 43.13 Mb Chr 6: 118.13 – 118.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The RETproto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. [5] RET loss of function mutations are associated with the development of Hirschsprung's disease, [6] [7] while gain of function mutations are associated with the development of various types of human cancer, including medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia.[ citation needed ]

Structure

RET is an abbreviation for "rearranged during transfection", as the DNA sequence of this gene was originally found to be rearranged within a 3T3 fibroblast cell line following its transfection with DNA taken from human lymphoma cells. [8] The human gene RET is localized to chromosome 10 (10q11.2) and contains 21 exons. [9]

The natural alternative splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43 and RET9 contain 51, 43 and 9 amino acids in their C-terminal tail respectively. [10] The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo as these are the most common isoforms in which RET occurs.

Common to each isoform is a domain structure. Each protein is divided into three domains: an N-terminal extracellular domain with four cadherin-like repeats and a cysteine-rich region, a hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase domain, which is split by an insertion of 27 amino acids. Within the cytoplasmic tyrosine kinase domain, there are 16 tyrosines (Tyrs) in RET9 and 18 in RET51. Tyr1090 and Tyr1096 are present only in the RET51 isoform. [11]

The extracellular domain of RET contains nine N-glycosylation sites. The fully glycosylated RET protein is reported to have a molecular weight of 170 kDa although it is not clear to which isoform this molecular weight relates. [12]

Kinase activation

RET is the receptor for GDNF-family ligands (GFLs). [13]

In order to activate RET, GFLs first need to form a complex with a glycosylphosphatidylinositol (GPI)-anchored co-receptor. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1, GFRα2, GFRα3, GFRα4) exhibit a specific binding activity for a specific GFLs. [14] Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Tyr900 and Tyr905 within the activation loop (A-loop) of the kinase domain have been shown to be autophosphorylation sites by mass spectrometry. [15] Phosphorylation of Tyr905 stabilizes the active conformation of the kinase, which, in turn, results in the autophosphorylation of other tyrosine residues mainly located in the C-terminal tail region of the molecule. [11]

RET dimer taken from crystal structure 2IVT Nonphos RET.jpeg
RET dimer taken from crystal structure 2IVT

The structure shown to the left was taken from the protein data bank code 2IVT. [5] The structure is that of a dimer formed between two protein molecules each spanning amino acids 703-1012 of the RET molecule, covering RETs intracellular tyrosine kinase domain. One protein molecule, molecule A is shown in yellow and the other, molecule B in grey. The activation loop is coloured purple and selected tyrosine residues in green. Part of the activation loop from molecule B is absent.

Phosphorylation of Tyr981 and the additional tyrosines Tyr1015, Tyr1062 and Tyr1096, not covered by the above structure, have been shown to be important to the initiation of intracellular signal transduction processes.

Role of RET signalling during development

Mice deficient in GDNF, GFRα1 or the RET protein itself exhibit severe defects in kidney and enteric nervous system development. This implicates RET signal transduction as key to the development of normal kidneys and the enteric nervous system. [11]

Clinical relevance

At least 26 disease-causing mutations in this gene have been discovered. [16] Activating point mutations in RET can give rise to the hereditary cancer syndrome known as multiple endocrine neoplasia type 2 (MEN 2). [17] There are three subtypes based on clinical presentation: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). [18] There is a high degree of correlation between the position of the point mutation and the phenotype of the disease.

Chromosomal rearrangements that generate a fusion gene, resulting in the juxtaposition of the C-terminal region of the RET protein with an N-terminal portion of another protein, can also lead to constitutive activation of the RET kinase. These types of rearrangements are primarily associated with papillary thyroid carcinoma (PTC) where they represent 10-20% of cases, and non-small cell lung cancer (NSCLC) where they represent 2% of cases. Several fusion partners have been described in the literature, and the most common ones across both cancer types include KIF5B, CCDC6 and NCOA4.

While older multikinase inhibitors such as cabozantinib or vandetanib showed modest efficacy in targeting RET-driven malignancies, newer selective inhibitors (such as selpercatinib and pralsetinib) have shown significant activity in both mutations and fusions. The results of the LIBRETTO-001 trial studying selpercatinib showed a progression-free survival of 17.5 months in previously treated RET-positive NSCLC, and 22 months for RET-positive thyroid cancers, which prompted an FDA approval for both these indications in May 2020. Several other selective RET inhibitors are under development, including TPX-0046, a macrocyclic inhibitor of RET and Src intended to inhibit mutations providing resistance to current inhibitors.

Disease database

The RET gene variant database at the University of Utah, identifies (as of November 2014) 166 mutations that are implicated in MEN2.

Interactions

RET proto-oncogene has been shown to interact with:

Related Research Articles

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<span class="mw-page-title-main">GRB7</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Glial cell line-derived neurotrophic factor</span> Protein-coding gene in the species Homo sapiens

Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the GDNF gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particularly GFRα1. It is also responsible for the determination of spermatogonia into primary spermatocytes, i.e. it is received by RET proto-oncogene (RET) and by forming gradient with SCF it divides the spermatogonia into two cells. As the result there is retention of spermatogonia and formation of spermatocyte.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

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<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">KIT (gene)</span> Mammalian protein and protein-coding gene

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<span class="mw-page-title-main">GRB10</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

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<span class="mw-page-title-main">HCK</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.

<span class="mw-page-title-main">GRB2-associated-binding protein 1</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.

<span class="mw-page-title-main">PIK3R2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GFRA1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">DDR1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GFRA2 (gene)</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000165731 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030110 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, et al. (November 2006). "Structure and chemical inhibition of the RET tyrosine kinase domain". The Journal of Biological Chemistry. 281 (44): 33577–33587. doi: 10.1074/jbc.M605604200 . PMID   16928683.
  6. ↑ Veiga-Fernandes H, Pachnis V (February 2017). "Neuroimmune regulation during intestinal development and homeostasis". Nature Immunology. 18 (2): 116–122. doi:10.1038/ni.3634. PMID   28092371. S2CID   5519816.
  7. ↑ Bahrami A, Joodi M, Moetamani-Ahmadi M, Maftouh M, Hassanian SM, Ferns GA, Avan A (January 2018). "Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application". Journal of Cellular Biochemistry. 119 (1): 28–33. doi:10.1002/jcb.26149. PMID   28543993. S2CID   12086686.
  8. ↑ Takahashi M, Ritz J, Cooper GM (September 1985). "Activation of a novel human transforming gene, ret, by DNA rearrangement". Cell. 42 (2): 581–588. doi:10.1016/0092-8674(85)90115-1. PMID   2992805. S2CID   13567823.
  9. ↑ Ceccherini I, Bocciardi R, Luo Y, Pasini B, Hofstra R, Takahashi M, Romeo G (November 1993). "Exon structure and flanking intronic sequences of the human RET proto-oncogene". Biochemical and Biophysical Research Communications. 196 (3): 1288–1295. doi:10.1006/bbrc.1993.2392. PMID   7902707.
  10. ↑ Myers SM, Eng C, Ponder BA, Mulligan LM (November 1995). "Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET". Oncogene. 11 (10): 2039–2045. PMID   7478523.
  11. 1 2 3 Arighi E, Borrello MG, Sariola H (2005). "RET tyrosine kinase signaling in development and cancer". Cytokine & Growth Factor Reviews. 16 (4–5): 441–467. doi:10.1016/j.cytogfr.2005.05.010. PMID   15982921.
  12. ↑ Takahashi M, Asai N, Iwashita T, Isomura T, Miyazaki K, Matsuyama M (November 1993). "Characterization of the ret proto-oncogene products expressed in mouse L cells". Oncogene. 8 (11): 2925–2929. PMID   8414495.
  13. ↑ Baloh RH, Enomoto H, Johnson EM, Milbrandt J (February 2000). "The GDNF family ligands and receptors - implications for neural development". Current Opinion in Neurobiology. 10 (1): 103–110. doi:10.1016/S0959-4388(99)00048-3. PMID   10679429. S2CID   32315320.
  14. ↑ Airaksinen MS, Titievsky A, Saarma M (May 1999). "GDNF family neurotrophic factor signaling: four masters, one servant?". Molecular and Cellular Neurosciences. 13 (5): 313–325. doi:10.1006/mcne.1999.0754. PMID   10356294. S2CID   46427535.
  15. ↑ Kawamoto Y, Takeda K, Okuno Y, Yamakawa Y, Ito Y, Taguchi R, et al. (April 2004). "Identification of RET autophosphorylation sites by mass spectrometry". The Journal of Biological Chemistry. 279 (14): 14213–14224. doi: 10.1074/jbc.M312600200 . PMID   14711813.
  16. ↑ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC   6901466 . PMID   31819097.
  17. ↑ Online Mendelian Inheritance in Man (OMIM): MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A - 171400
  18. ↑ Qi XP, Ma JM, Du ZF, Ying RB, Fei J, Jin HY, et al. (2011). "RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family". PLOS ONE. 6 (5): e20353. Bibcode:2011PLoSO...620353Q. doi: 10.1371/journal.pone.0020353 . PMC   3105051 . PMID   21655256.
  19. ↑ Murakami H, Yamamura Y, Shimono Y, Kawai K, Kurokawa K, Takahashi M (September 2002). "Role of Dok1 in cell signaling mediated by RET tyrosine kinase". The Journal of Biological Chemistry. 277 (36): 32781–32790. doi: 10.1074/jbc.M202336200 . PMID   12087092.
  20. ↑ Crowder RJ, Enomoto H, Yang M, Johnson EM, Milbrandt J (October 2004). "Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth". The Journal of Biological Chemistry. 279 (40): 42072–42081. doi:10.1074/jbc.M403726200. PMID   15286081.
  21. ↑ Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K, Birchmeier W (July 2001). "Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation". The Journal of Cell Biology. 154 (2): 345–354. doi:10.1083/jcb.200102032. PMC   2150770 . PMID   11470823.
  22. ↑ Klein RD, Sherman D, Ho WH, Stone D, Bennett GL, Moffat B, et al. (June 1997). "A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor". Nature. 387 (6634): 717–721. Bibcode:1997Natur.387..717K. doi: 10.1038/42722 . PMID   9192898. S2CID   4360246.
  23. ↑ Cik M, Masure S, Lesage AS, Van Der Linden I, Van Gompel P, Pangalos MN, et al. (September 2000). "Binding of GDNF and neurturin to human GDNF family receptor alpha 1 and 2. Influence of cRET and cooperative interactions". The Journal of Biological Chemistry. 275 (36): 27505–27512. doi: 10.1074/jbc.M000306200 . PMID   10829012.
  24. 1 2 Pandey A, Duan H, Di Fiore PP, Dixit VM (September 1995). "The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10". The Journal of Biological Chemistry. 270 (37): 21461–21463. doi: 10.1074/jbc.270.37.21461 . PMID   7665556.
  25. ↑ Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM (May 1996). "Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7". The Journal of Biological Chemistry. 271 (18): 10607–10610. doi:10.1074/jbc.271.18.10607. PMID   8631863.
  26. 1 2 Borrello MG, Pelicci G, Arighi E, De Filippis L, Greco A, Bongarzone I, et al. (June 1994). "The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins". Oncogene. 9 (6): 1661–1668. PMID   8183561.
  27. ↑ Arighi E, Alberti L, Torriti F, Ghizzoni S, Rizzetti MG, Pelicci G, et al. (February 1997). "Identification of Shc docking site on Ret tyrosine kinase". Oncogene. 14 (7): 773–782. doi: 10.1038/sj.onc.1200896 . PMID   9047384.
  28. ↑ Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE (November 2004). "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Molecular and Cellular Biology. 24 (21): 9390–9400. doi:10.1128/MCB.24.21.9390-9400.2004. PMC   522220 . PMID   15485908.
  29. ↑ Hwang JH, Kim DW, Suh JM, Kim H, Song JH, Hwang ES, et al. (June 2003). "Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation". Molecular Endocrinology. 17 (6): 1155–1166. doi:10.1210/me.2002-0401. PMID   12637586.
  30. ↑ Schuringa JJ, Wojtachnio K, Hagens W, Vellenga E, Buys CH, Hofstra R, Kruijer W (August 2001). "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene. 20 (38): 5350–5358. doi: 10.1038/sj.onc.1204715 . PMID   11536047.

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