ROMANO, Roberta, Matteo CALCAGNILE, Azzurra MARGIOTTA, Lorenzo FRANCI, Mario CHIARIELLO, Pietro ALIFANO and Cecilia BUCCI. RAB7A Regulates Vimentin Phosphorylation through AKT and PAK. Cancers. Basel: MDPI, 2021, vol. 13, No 9, p. 1-22. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers13092220.
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Basic information
Original name RAB7A Regulates Vimentin Phosphorylation through AKT and PAK
Authors ROMANO, Roberta, Matteo CALCAGNILE, Azzurra MARGIOTTA (380 Italy, belonging to the institution), Lorenzo FRANCI, Mario CHIARIELLO, Pietro ALIFANO and Cecilia BUCCI (guarantor).
Edition Cancers, Basel, MDPI, 2021, 2072-6694.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30204 Oncology
Country of publisher Switzerland
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 6.575
RIV identification code RIV/00216224:14110/21:00121584
Organization unit Faculty of Medicine
Doi http://dx.doi.org/10.3390/cancers13092220
UT WoS 000649895300001
Keywords in English cell migrationintermediate filamentsRAC1beta-cateninNF-kBcofilin
Tags 14110513, rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 19/8/2021 12:49.
Abstract
RAB7A (RAs-related in Brain 7A) is a master regulator of intracellular traffic controlling transport to late endosomes and lysosomes, two organelles of the endocytic pathway important for degradation. Thanks to this function, RAB7A is also involved in cellular processes linked to cancer, such as apoptosis, cytoskeletal reorganization, and cell migration. Therefore, the interest in the role of RAB7A in cancer progression is increasing. Previously, we demonstrated that RAB7A regulates phosphorylation and assembly of vimentin, a cytoskeletal intermediate filament protein, which is also an important mesenchymal marker of cancer cells. The aim of the present study is the identification of the kinases responsible for vimentin phosphorylation whose activity is affected by the modulation of RAB7A expression. We found that RAB7A is able to regulate AKT (also called protein kinase B or PKB) and PAK1 (P21-Activated Kinase 1) and several of their downstream effectors, which control proliferation, apoptosis, survival, migration, and invasion. These data suggest that RAB7A could have a key role in cancer development. RAB7A is a small GTPase that controls the late endocytic pathway but also cell migration through RAC1 (Ras-related C3 botulinum toxin substrate 1) and vimentin. In fact, RAB7A regulates vimentin phosphorylation at different sites and vimentin assembly, and, in this study, we identified vimentin domains interacting with RAB7A. As several kinases could be responsible for vimentin phosphorylation, we investigated whether modulation of RAB7A expression affects the activity of these kinases. We discovered that RAB7A regulates AKT and PAK1, and we demonstrated that increased vimentin phosphorylation at Ser38 (Serine 38), observed upon RAB7A overexpression, is due to AKT activity. As AKT and PAK1 are key regulators of several cellular events, we investigated if RAB7A could have a role in these processes by modulating AKT and PAK1 activity. We found that RAB7A protein levels affected beta-catenin and caspase 9 expression. We also observed the downregulation of cofilin-1 and decreased matrix metalloproteinase 2 (MMP2) activity upon RAB7A silencing. Altogether these results demonstrate that RAB7A regulates AKT and PAK1 kinases, affecting their downstream effectors and the processes they regulate, suggesting that RAB7A could have a role in a number of cancer hallmarks.
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