ArticleOncogene2006
Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations.
Article in Oncogene, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02363647 (Personalized Cancer Therapy for Patients With Metastatic Medullary Thyroid or Metastatic Colon Cancer), which is not on this map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Personalized Cancer Therapy for Patients With Metastatic Medullary Thyroid or Metastatic Colon Cancer
Who cites it
24 citing papers in PubMed, 61 citations in OpenAlex.
- RET receptor tyrosine kinase architecture, assemblies, and activation.Endocrine-related cancer · 2026Review
- Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions.Disease models & mechanisms · 2026Article
- Sporadic medullary thyroid carcinoma with a rare RET transmembrane domain mutation (A641R) that responds to selpercatinib.The oncologist · 2025Article
- Optogenetic dissection of RET signaling reveals robust activation of ERK and enhanced filopodia-like protrusions of regenerating axons.Molecular brain · 2023Article
- Parathyroid Tumors: Molecular Signatures.International journal of molecular sciences · 2021Review
- Functional impact of a germline RET mutation in alveolar rhabdomyosarcoma.Cold Spring Harbor molecular case studies · 2021Article
- Article
- Next-generation sequencing analysis of receptor-type tyrosine kinase genes in surgically resected colon cancer: identification of gain-of-function mutations in the RET proto-oncogene.Journal of experimental & clinical cancer research : CR · 2018Article
- Screening for transmembrane association in divisome proteins using TOXGREEN, a high-throughput variant of the TOXCAT assay.Biochimica et biophysica acta · 2016Article
- Discovery and functional characterization of a germline, CSF2RB-activating mutation in leukemia.Leukemia · 2016Article
- Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction.The Journal of biological chemistry · 2016Article
- Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma.Endocrine · 2015Article
- Mutation-introduced dimerization of receptor tyrosine kinases: from protein structure aberrations to carcinogenesis.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Review
- Normal activation of discoidin domain receptor 1 mutants with disulfide cross-links, insertions, or deletions in the extracellular juxtamembrane region: mechanistic implications.The Journal of biological chemistry · 2014Article
- Central role of RET in thyroid cancer.Cold Spring Harbor perspectives in biology · 2013Review
- Plot protein: visualization of mutations.Journal of clinical bioinformatics · 2013Article
- Structure and physiology of the RET receptor tyrosine kinase.Cold Spring Harbor perspectives in biology · 2013Review
- The Hirschsprung's-multiple endocrine neoplasia connection.Clinics (Sao Paulo, Brazil) · 2012Review
- Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia.Nature genetics · 2011Article
- Protein-tyrosine phosphatase SHP2 contributes to GDNF neurotrophic activity through direct binding to phospho-Tyr687 in the RET receptor tyrosine kinase.The Journal of biological chemistry · 2010Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In patients with medullary thyroid carcinoma (MTC) and type 2A multiple endocrine neoplasia (MEN2A), mutations of cysteine residues in the extracellular juxtamembrane region of the RET receptor tyrosine kinase cause the formation of covalent receptor dimers linked by intermolecular disulfide bonds between unpaired cysteines, followed by oncogenic activation of the RET kinase. The close proximity to the plasma membrane of the affected cysteine residues prompted us to investigate the possible role of the transmembrane (TM) domain of RET (RET-TM) in receptor-receptor interactions underlying dimer formation. Strong self-association of the RET-TM was observed in a biological membrane. Mutagenesis studies indicated the involvement of the evolutionary conserved residues Ser-649 and Ser-653 in RET-TM oligomerization. Unexpectedly, RET-TM interactions were also abrogated in the A639G/A641R double mutant, first identified in a sporadic case of MTC. In agreement with this, no transforming activity could be detected in full-length RET carrying the A639G and A641R mutations, which remained fully responsive to glial cell-line-derived neurotrophic factor (GDNF) stimulation. When introduced in the context of C634R - a cysteine replacement that is prevalent in MEN2A cases - the A639G/A641R mutations significantly reduced dimer formation and transforming activity in this otherwise highly oncogenic RET variant. These data suggest that a strong propensity to self-association in the RET-TM underlies - and may be required for - dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteine residues implicated in MEN2A and MTC syndromes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.