دورية أكاديمية
Nuclear focal adhesion kinase induces APC/C activator protein CDH1-mediated cyclin-dependent kinase 4/6 degradation and inhibits melanoma proliferation.
| العنوان: | Nuclear focal adhesion kinase induces APC/C activator protein CDH1-mediated cyclin-dependent kinase 4/6 degradation and inhibits melanoma proliferation. |
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| المؤلفون: | Murphy JM; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA., Jeong K; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA., Ahn EE; Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA., Lim SS; Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: stlim@uab.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2022 Jun; Vol. 298 (6), pp. 102013. Date of Electronic Publication: 2022 May 05. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Antigens, CD*/genetics , Antigens, CD*/metabolism , Cadherins*/genetics , Cadherins*/metabolism , Cyclin-Dependent Kinase 6*/metabolism , Focal Adhesion Protein-Tyrosine Kinases*/metabolism , Melanoma*/genetics , Melanoma*/physiopathology, Anaphase-Promoting Complex-Cyclosome/metabolism ; Cell Proliferation ; Cyclin-Dependent Kinase 4/metabolism ; Humans ; United States |
| مستخلص: | Dysregulation of cyclin-dependent kinases (CDKs) can promote unchecked cell proliferation and cancer progression. Although focal adhesion kinase (FAK) contributes to regulating cell cycle progression, the exact molecular mechanism remains unclear. Here, we found that FAK plays a key role in cell cycle progression potentially through regulation of CDK4/6 protein expression. We show that FAK inhibition increased its nuclear localization and induced G1 arrest in B16F10 melanoma cells. Mechanistically, we demonstrate nuclear FAK associated with CDK4/6 and promoted their ubiquitination and proteasomal degradation through recruitment of CDC homolog 1 (CDH1), an activator and substrate recognition subunit of the anaphase-promoting complex/cyclosome E3 ligase complex. We found the FAK N-terminal FERM domain acts as a scaffold to bring CDK4/6 and CDH1 within close proximity. However, overexpression of nonnuclear-localizing mutant FAK FERM failed to function as a scaffold for CDK4/6 and CDH1. Furthermore, shRNA knockdown of CDH1 increased CDK4/6 protein expression and blocked FAK inhibitor-induced reduction of CDK4/6 in B16F10 cells. In vivo, we show that pharmacological FAK inhibition reduced B16F10 tumor size, correlating with increased FAK nuclear localization and decreased CDK4/6 expression compared with vehicle controls. In patient-matched healthy skin and melanoma biopsies, we found FAK was mostly inactive and nuclear localized in healthy skin, whereas melanoma lesions showed increased active cytoplasmic FAK and elevated CDK4 expression. Taken together, our data demonstrate that FAK inhibition blocks tumor proliferation by inducing G1 arrest, in part through decreased CDK4/6 protein stability by nuclear FAK. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | R01 CA190688 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: CDH1; CDK4/6; FAK; melanoma |
| المشرفين على المادة: | 0 (Antigens, CD) 0 (CDH1 protein, human) 0 (Cadherins) EC 2.3.2.27 (Anaphase-Promoting Complex-Cyclosome) EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases) EC 2.7.11.22 (CDK6 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) |
| تواريخ الأحداث: | Date Created: 20220507 Date Completed: 20220629 Latest Revision: 20240425 |
| رمز التحديث: | 20240425 |
| مُعرف محوري في PubMed: | PMC9163754 |
| DOI: | 10.1016/j.jbc.2022.102013 |
| PMID: | 35525274 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2022.102013 |