ArticleMolecular and cellular biology2003
Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region.
Article in Molecular and cellular biology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 158 citations in OpenAlex.
- Golgi Retention and Oncogenic Signaling of KIT Tyrosine Kinase in Gastrointestinal Stromal Tumor.Sub-cellular biochemistry · 2026Review
- Well-differentiated systemic mastocytosis: Genetics, mast cell immunophenotypes, and KIT autophosphorylation.The Journal of allergy and clinical immunology · 2025Article
- Gastrointestinal Malignancy: Genetic Implications to Clinical Applications.Cancer treatment and research · 2024Review
- Bioinformatic analysis of KIT juxtamembrane domain mutations in Syrian GIST patients: jigsaw puzzle completed.Journal of the Egyptian National Cancer Institute · 2023Article
- Pathologic complete response to neoadjuvant imatinib of a gastric stromal tumor with concomitant mutations inClinical case reports · 2023Article
- Article
- c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights.OncoTargets and therapy · 2023Review
- Role and significance of c-KIT receptor tyrosine kinase in cancer: A review.Bosnian journal of basic medical sciences · 2022Review
- The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT.International journal of molecular sciences · 2022Article
- NovelCold Spring Harbor molecular case studies · 2019Article
- N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells.Cell communication and signaling : CCS · 2019Article
- ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.Cancer research · 2019Article
- Functional Properties ofClinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- RET rearrangements are actionable alterations in breast cancer.Nature communications · 2018Article
- Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth.Molecular oncology · 2018Article
- Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells.Journal of cancer research and clinical oncology · 2017Article
- RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements.Cell reports · 2016Article
- Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.Oncotarget · 2016Article
- Oncogenic KIT mutations in different exons lead to specific changes in melanocyte phospho-proteome.Journal of proteomics · 2016Article
- A survival Kit for pancreatic beta cells: stem cell factor and c-Kit receptor tyrosine kinase.Diabetologia · 2015Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic studies have implicated the cytosolic juxtamembrane region of the Kit receptor tyrosine kinase as an autoinhibitory regulatory domain. Mutations in the juxtamembrane domain are associated with cancers, such as gastrointestinal stromal tumors and mastocytosis, and result in constitutive activation of Kit. Here we elucidate the biochemical mechanism of this regulation. A synthetic peptide encompassing the juxtamembrane region demonstrates cooperative thermal denaturation, suggesting that it folds as an autonomous domain. The juxtamembrane peptide directly interacted with the N-terminal ATP-binding lobe of the kinase domain. A mutation in the juxtamembrane region corresponding to an oncogenic form of Kit or a tyrosine-phosphorylated form of the juxtamembrane peptide disrupted the stability of this domain and its interaction with the N-terminal kinase lobe. Kinetic analysis of the Kit kinase harboring oncogenic mutations in the juxtamembrane region displayed faster activation times than the wild-type kinase. Addition of exogenous wild-type juxtamembrane peptide to active forms of Kit inhibited its kinase activity in trans, whereas the mutant peptide and a phosphorylated form of the wild-type peptide were less effective inhibitors. Lastly, expression of the Kit juxtamembrane peptide in cells which harbor an oncogenic form of Kit inhibited cell growth in a Kit-specific manner. Together, these results show the Kit kinase is autoinhibited through an intramolecular interaction with the juxtamembrane domain, and tyrosine phosphorylation and oncogenic mutations relieved the regulatory function of the juxtamembrane domain.
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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.