Annexin II-dependent actin remodelling evoked by hydrogen peroxide requires the metalloproteinase/sphingolipid pathway

Abstract

Actin remodeling is a dynamic process associated with cell shape modification occurring during cell cycle and proliferation. Oxidative stress plays a role in actin reorganization via various systems including p38MAPK. Beside, the mitogenic response evoked by hydrogen peroxide (H2O2) in fibroblasts and smooth muscle cells (SMC) involves the metalloproteinase (MMPs)/sphingomyelinase 2 (nSMase2) signaling pathway. The aim of this work was to investigate whether this system plays a role in actin remodeling induced by H2O2.Low H2O2 dose (5 µM) rapidly triggered a signaling cascade leading to nSMase2 activation, src and annexin 2 (AnxA2) phosphorylation, and actin remodeling, in fibroblasts and SMC. These events were blocked by pharmacological inhibitors of MMPs (Ro28-2653) and p38MAPK (SB203580), and were lacking in MMP2−/− and in nSMase2-mutant (fro) fibroblasts. Likewise, H2O2 was unable to induce actin remodeling in fro and MMP2−/− fibroblasts or in cells pretreated with p38MAPK, or MMP inhibitors. Finally we show that nSMase2 activation by H2O2, depends on MMP2 and p38MAPK, and is required for the src-dependent phosphorylation of AnxA2, and actin remodeling.Taken together, these findings indicate for the first time that AnxA2 phosphorylation and actin remodeling evoked by oxidative stress depend on the sphingolipid pathway, via MMP2 and p38MAPK.

Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation

“…; Cinq‐Frais et al . ). Given the role of the SMPD3 pathway in exosome biogenesis, we tested if SMPD3 is involved in exosome secretion by VSMCs and found that inhibition of SMPD3 reduced exosome production (Trajkovic et al .…”

Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of Annexin A2

“…Upregulation of AnxA2 in response to H 2 O 2 -induced oxidative stress has been reported for several cell types ( Tanaka et al, 2004 ; Kim et al, 2011 ; Madureira et al, 2011 ) and its phosphorylation is also increased under these conditions ( Tanaka et al, 2004 ; Matsuda et al, 2006 ). A recent study concluded that H 2 O 2 -induced Tyr23 phosphorylation of AnxA2 occurs through the metalloproteinase and sphingolipid pathways ( Cinq-Frais et al, 2015 ). The protein has also been shown to reside in the nucleus, where it contributes to the protection of DNA in cells exposed to H 2 O 2 and other genotoxic agents ( Madureira et al, 2012 ).…”

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

“…ANXA2 belongs to the calcium-conducting annexin family, which has been reported to activate MAPK signaling and promote metastasis in tumor cells. Tyrosine phosphorylation (Tyr23) of ANXA2 was required for ERK1/2 activation [ 30 , 41 , 42 ]. In RalA-overexpressing MDA231 cells, we observed that ANXA2 knockdown indeed reduce p-ERK1/2 (Fig.…”

“…ANXA2, an accessory protein that belongs to the calcium-conducting annexin family [ 25 ], is highly expressed in breast tumor tissues [ 26 ]. Tyr23 Phosphorylation of ANXA2 by Src tyrosine kinase is an important post-translational modification of ANXA2, and p-ANXA2 has significant effects on ERK signal activation, EMT, and metastasis in tumor cells [ 27 – 30 ]. However, little is known regarding the interaction between RalA, ANXA2 and Src in BC.…”