Extracellular Signal-regulated Kinase Mediates Phosphorylation of Tropomyosin-1 to Promote Cytoskeleton Remodeling in Response to Oxidative Stress: Impact on Membrane Blebbing

Houle, François; Rousseau, Stéphane; Morrice, Nick; Luc, Mario; Mongrain, Sébastien; Turner, Christopher E.; Tanaka, Sakae; Moreau, Pierre; Huot, Jacques

doi:10.1091/mbc.e02-04-0235

Cited by 98 publications

(84 citation statements)

References 51 publications

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“…Moreover, our data suggest that the inhibition of MR-1 expression suppresses HepG2 cell adhesion (Fig. 3, C and D), which we think is attributed to the inhibition of MLC2 phosphorylation, consistent with other reports that MLCK inhibition can prevent the formation of focal adhesions in human umbilical vein endothelial cells (30), and the inhibition of myosin II function can suppress PC cell migration and adhesion (31). When MR-1 is knocked down stably by the transfection of MR-1-siRNA-expressing plasmid and cell spreading on FN are reduced (Fig.…”

Section: Discussionsupporting

confidence: 92%

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

Ren

Jin

Bian

et al. 2008

Journal of Biological Chemistry

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The key of cell migration process on solid substrates is phosphorylation of myosin light chain-2 (MLC2), which is implicated in a variety of intracellular functions. The previous data show that MLC2 interacts with a novel human gene, myofibrillogenesis regulator 1 (MR-1). Here, we reported that MR-1 was specially overexpressed in human hepatoma HepG2 cells. Transient treatment of cells with small interfering RNA (siRNA) against MR-1 or stable transfection of cells with plasmid expressing MR-1-siRNA led to inhibitions of cell proliferation, migration, and adhesion. Following down-regulation of MR-1, the phosphorylations of MLC2, focal adhesion kinase (FAK), and Akt were dramatically decreased, and the formation of stress fiber was destroyed by MR-1-siRNAs in hepatoma HepG2 cells. In addition, exogenous MR-1-induced as well as inherent phosphorylations of FAK and Akt were decreased by MLC kinase (MLCK) inhibitor, and F-actin polymerization inhibitor also decreased phosphorylations of FAK and Akt. Correspondingly, MR-1-enhanced migration of cells was also inhibited by these two inhibitors. These indicated that MLC2 activation and intact actin cytoskeleton were pivotal for MR-1 function. In vivo data showed that MR-1-siRNA markedly inhibited growth of human HepG2. This study suggested that overexpression of MR-1 was associated with cancer cell proliferation and migration through MLC2 and that MR-1 might be a potential cancer therapeutic target.Cancer progression from a primary tumor to secondary metastasis is a highly complex process involving alteration of gene expression, acquisition of cell motility, interaction with extracellular matrix (ECM), 3 change in cell adhesion, and expression of ECM-degrading protease (1). Cell migration is a critical step in tumor metastasis. Cancer cells move within tissues during invasion and metastasis by their own motility, and cell migration involves multiple processes that are regulated by various signaling molecules (2). It results from a dynamic interplay between the substrate and cytoskeleton protein located at the focal adhesion complex (3). It is known that cells exert force propelling the cell forward by contraction of the actin cytoskeleton through activation of myosin II (4). The actin-myosin II interaction in non-muscle cells is regulated by the phosphorylation of MLC2 at serine-19 (5). MLC2 dephosphorylation can induce apoptosis (6), and inhibitor of MLCK can abrogate MLC2 phosphorylation, cell polarization, and migration (7). MLC2 is also involved in the activation of mid-G 1 phase cyclin D1 expression (8, 9). It has been reported that hyperphosphorylated MLC2 induces stress fiber formation and integrin clustering that link cell surface cytoskeletal proteins such as FAK to actin (10, 11). FAK is a member of the focal adhesions that mediates integrin-mediated signal transduction associated with a variety of cellular functions including cellular proliferation, migration, and adhesion (12). Downstream signaling pathways implicated in FAK signaling include the Jun N-termin...

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Section: Discussionsupporting

confidence: 92%

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

Ren

Jin

Bian

et al. 2008

Journal of Biological Chemistry

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“…Stress fibres are constituted of an association of actin with myosin (Zhong et al, 1998). The association is triggered by the phosphorylation of myosin light chain in response to increase contractile forces generated in the cells by actin polymerization (Mehta and Gunst, 1999;Houle et al, 2003;Shaw et al, 2003). In accordance, we found that phosphorylation of MLC is impaired by inhibiting actin polymerization by cytochalasin D. Given that p38 activation mediates actin polymerization in response to VEGF and oxidative stress (Huot et al, , 1998Rousseau et al, 1997Rousseau et al, , 2000, our results suggest that the activation of p38 induces the formation of stress fibres and thereby interendothelial opening by leading to actin-polymerization-mediated phosphorylation of MLC.…”

Section: Discussionmentioning

confidence: 99%

Regulation of transendothelial migration of colon cancer cells by E-selectin-mediated activation of p38 and ERK MAP kinases

2006

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The invasive properties of cancer cells depend on their intrinsic motile potential and on their ability to breach the endothelial barrier. In the present work, we investigated the mechanisms by which adhesion of colon cancer cells to E-selectin expressed by endothelial cells regulates the barrier function of these cells and modulates transmigration of cancer cells. We found that the stimulation of E-selectin by activating antibodies or the adhesion of HT-29 cells results in an increase in the activity of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases. In turn, the activation of p38 and ERK enhances transendothelial permeability and migration of HT-29 cells. We also obtained evidence suggesting that p38-mediated increase in transendothelial migration of cancer cells depends on a myosin light chain phosphorylation-mediated formation of stress fibres. On the other hand, the activation of ERK by E-selectin modulates the opening of interendothelial spaces by initiating the activation of Src kinase activities and the dissociation of the VE-cadherin/b-catenin complex. We conclude that activation of E-selectin by adhering cancer cells is an important process that regulates the extravasation of colon cancer cells by initiating p38-and ERK-dependent mechanisms that both contribute to regulate the integrity of the endothelial layer.

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“…34). TM1 can be phosphorylated (35) and acetylated (36) and both modifications enhance actin filament binding. Upon experimental cellular transformation, TM1 expression is often found to be down-regulated and correlates with the lack of actin stress fiber formation (37).…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C

et al. 2004

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Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of ␤-catenin and stimulated the expression of the ␤-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.

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Extracellular Signal-regulated Kinase Mediates Phosphorylation of Tropomyosin-1 to Promote Cytoskeleton Remodeling in Response to Oxidative Stress: Impact on Membrane Blebbing

Cited by 98 publications

References 51 publications

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

Regulation of transendothelial migration of colon cancer cells by E-selectin-mediated activation of p38 and ERK MAP kinases

Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C

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