J 2021

RAB7A Regulates Vimentin Phosphorylation through AKT and PAK

ROMANO, Roberta, Matteo CALCAGNILE, Azzurra MARGIOTTA, Lorenzo FRANCI, Mario CHIARIELLO et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 6.575

RIV identification code

RIV/00216224:14110/21:00121584

Organization unit

Faculty of Medicine

DOI

UT WoS

000649895300001

Keywords in English

cell migrationintermediate filamentsRAC1beta-cateninNF-kBcofilin

Tags

Tags

International impact, Reviewed
Změněno: 19/8/2021 12:49, Mgr. Tereza Miškechová

Abstract

V originále

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.