RAB7A Regulates Vimentin Phosphorylation through AKT and PAK

Abstract

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.

Analysis of the multi-physiological and functional mechanism of wheat alkylresorcinols based on reverse molecular docking and network pharmacology

“…81 RAB7A is a small GTPase that controls the late endocytosis pathway of cells. 82 In addition, PPARG, PPARA, CYP11A1, and FABP4 among the captured targets are also associated with cholesterol storage and metabolism (GO:0010887, GO:0008203, and GO:0042632). Some studies have reported that ARs increase cholesterol excretion in male mice.…”

HrpA anchors meningococci to the dynein motor and affects the balance between apoptosis and pyroptosis

“…Pull-down experiments were carried out as described [ 23 , 24 ]. Briefly, purified His-tagged HrpA-M2 or HrpA-M3 peptides were bound to Ni–NTA resin for 1 h at 4 °C.…”

Pathophysiological Role of Vimentin Intermediate Filaments in Lung Diseases

“…Vimentin intermediate filaments can indirectly regulate permeability through their functions as endosomal trafficking regulators. Vimentin intermediate filaments interact with endocytosis regulator proteins, namely Rab GTPase family proteins ( Cogli et al, 2013 ; Margiotta et al, 2017 ; Romano et al, 2021 ). During edema, the inter-endothelial junctions are maintained by vascular endothelial cadherins (VE-cadherin).…”

“…Recently, a study demonstrated Rab GTPases, Rab4, -7, and -9 regulate vascular permeability through enhanced VE-cadherin expression at the interendothelial junction ( Chichger et al, 2016 ). Rab7a and Rab9 interactions with vimentin are indispensable for efficient endosome trafficking ( Cogli et al, 2013 ; Margiotta et al, 2017 ; Romano et al, 2021 ). It is reasonable to assume that the VE-cadherin exosomes require Rab7 and Rab9 interactions with vimentin intermediate filaments for their successful shuttling to the surface of endothelial cells.…”

“…Rab7a interacts directly with vimentin, and this interaction modulates vimentin phosphorylation and assembly ( Cogli et al, 2013 ). Rab7a depleted cells have an abundance of insoluble Vimentin intermediate filaments, and defective endosomal trafficking ( Romano et al, 2021 ). Phosphorylation of Vimentin intermediate filaments at Ser459 by Polo-like kinase 1 (Plk1) inhibits the endolytic fusion during mitosis ( Ikawa et al, 2014 ).…”