Fibronectin Matrix Regulates Activation of RHO and CDC42 GTPases and Cell Cycle Progression

Bourdoulous, Sandrine; Orend, Gertraud; MacKenna, Deidre A.; Pasqualini, Renata; Ruoslahti, Erkki

doi:10.1083/jcb.143.1.267

Cited by 215 publications

(198 citation statements)

References 60 publications

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“…This may account for the observation of stress fiber formation after an extended period of spreading on either mAb D120 or mAb N143. Because the involvement of cdc42 and/or rac in cellular signaling phenomena can be assessed by assaying for the activation of specific downstream kinases (Manser et al, 1993(Manser et al, , 1994Martin et al, 1995;Yang and Cerione, 1997;Bourdoulous et al, 1998;Price et al, 1998) or through the use of dominant negative mutants of the two GTPases Nobes and Hall, 1995;Bourdoulous et al, 1998;Price et al, 1998), we can plan future experiments to test more directly the hypothesis that these two molecules are differentially activated upon engagement of distinct epitopes of NG2.…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Fang

Burg

Barritt

et al. 1999

MBoC

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Cells expressing the NG2 proteoglycan can attach, spread, and migrate on surfaces coated with NG2 mAbs, demonstrating that engagement of NG2 can trigger the cytoskeletal rearrangements necessary for changes in cell morphology and motility. Engagement of different epitopes of the proteoglycan results in distinct forms of actin reorganization. On mAb D120, the cells contain radial actin spikes characteristic of filopodial extension, whereas on mAb N143, the cells contain cortical actin bundles characteristic of lamellipodia. Cells that express NG2 variants lacking the transmembrane and cytoplasmic domains are unable to spread or migrate on NG2 mAb-coated surfaces, indicating that these portions of the molecule are essential for NG2-mediated signal transduction. Cells expressing an NG2 variant lacking the C-terminal half of the cytoplasmic domain can still spread normally on mAbs D120 and N143, suggesting that the membraneproximal cytoplasmic segment is responsible for this process. In contrast, this variant migrates poorly on mAb D120 and exhibits abnormal arrays of radial actin filaments decorated with fascin during spreading on this mAb. The C-terminal portion of the NG2 cytoplasmic domain, therefore, may be involved in regulating molecular events that are crucial for cell motility.

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Section: Discussionmentioning

confidence: 99%

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Fang

Burg

Barritt

et al. 1999

MBoC

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“…It is reasonable to propose that COX-2 expression is induced during cell adhesion because ERK1/2 is activated during adhesion, and induction of COX-2 expression by growth-factor mitogens is mediated by ERK1/2 (Miyamoto et al, 1996;Cybulsky and McTavish, 1997;Hwang et al, 1997;Karim et al, 1997;Langholz et al, 1997;Bourdoulous et al, 1998;Miller et al, 1998;Sheng et al, 1998;Adderley and Fitzgerald, 1999). Our measurements indicate that COX-2 protein appeared in control cells at ϳ45-60 min postplating, after spreading was essen-tially complete, whereas blockade of ERK1/2 prevented induction and synthesis of COX-2 ( Figure 10B).…”

Section: Discussionmentioning

confidence: 99%

“…ERK1/2 was seen to be rapidly phosphorylated within 5 min of plating and then dephosphorylated by 30 min postplating in control cells (C), whereas the amount of total ERK did not change over time ( Figure 10A). This ERK1/2 activation by phosphorylation is a well-known effect of integrin-mediated cell interaction with ECM (Miyamoto et al, 1996;Cybulsky and McTavish, 1997;Langholz et al, 1997;Bourdoulous et al, 1998;Crawford and Jacobson, 1998). Addition of 50 M PD98059 prevented phosphorylation as shown by the PD lanes.…”

Section: Arachidonate and Erk In Cell Adhesionmentioning

confidence: 99%

Modulation of Cell-Substrate Adhesion by Arachidonic Acid: Lipoxygenase Regulates Cell Spreading and ERK1/2-inducible Cyclooxygenase Regulates Cell Migration in NIH-3T3 Fibroblasts

Stockton

Jacobson

2001

MBoC

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Adhesion of cells to an extracellular matrix is characterized by several discrete morphological and functional stages beginning with cell-substrate attachment, followed by cell spreading, migration, and immobilization. We find that although arachidonic acid release is rate-limiting in the overall process of adhesion, its oxidation by lipoxygenase and cyclooxygenases regulates, respectively, the cell spreading and cell migration stages. During the adhesion of NIH-3T3 cells to fibronectin, two functionally and kinetically distinct phases of arachidonic acid release take place. An initial transient arachidonate release occurs during cell attachment to fibronectin, and is sufficient to signal the cell spreading stage after its oxidation by 5-lipoxygenase to leukotrienes. A later sustained arachidonate release occurs during and after spreading, and signals the subsequent migration stage through its oxidation to prostaglandins by newly synthesized cyclooxygenase-2. In signaling migration, constitutively expressed cyclooxygenase-1 appears to contribute ϳ25% of prostaglandins synthesized compared with the inducible cyclooxygenase-2. Both the second sustained arachidonate release, and cyclooxygenase-2 protein induction and synthesis, appear to be regulated by the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK)1/2. The initial cell attachment-induced transient arachidonic acid release that signals spreading through lipoxygenase oxidation is not sensitive to ERK1/2 inhibition by PD98059, whereas PD98059 produces both a reduction in the larger second arachidonate release and a blockade of induced cyclooxygenase-2 protein expression with concomitant reduction of prostaglandin synthesis. The second arachidonate release, and cyclooxygenase-2 expression and activity, both appear to be required for cell migration but not for the preceding stages of attachment and spreading. These data suggest a bifurcation in the arachidonic acid adhesion-signaling pathway, wherein lipoxygenase oxidation generates leukotriene metabolites regulating the spreading stage of cell adhesion, whereas ERK 1/2-induced cyclooxygenase synthesis results in oxidation of a later release, generating prostaglandin metabolites regulating the later migration stage. INTRODUCTIONCell adhesion to the extracellular matrix (ECM) is a sequential process of discrete temporal stages. Detached cells, e.g., leukocytes, metastasized cancer cells, or suspension-cultured cells, initially attach to an ECM protein substrate by means of plasma membrane receptors. Attached cells then undergo spreading, which results in flattening and the formation of focal adhesions. Subsequently, some cell types undergo migration on the ECM, whereas others remain stationary. Each of these stages of adhesion, i.e., attachment, spreading, migration, and immobilization, involves changes in morphology and cytoskeletal structure that are regulated by incompletely defined protein kinase and lipid second messenger pathways (reviewed in Huttenlocher et al., 1995;Heidemann an...

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“…Accordingly, a role for RhoA in uPAR transcription and expression has been described (Muller et al, 2000). Activation of oncogenic RhoA by extracellular matrix signals such as laminin or fibronectin stimulates transcription of the uPAR gene promoter region and results in enhanced motility and invasiveness of cells (Bourdoulous et al, 1998). Which RhoA-modulated transcription factors are involved in this process is unknown, but the presence of AP-1-and NF-B-responsive elements in the uPAR promoter points to a role of both TFs in this process (Dang et al, 1999;Wang et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Benitah¹,

Valerón²,

Rui

et al. 2003

MBoC

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The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility

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Fibronectin Matrix Regulates Activation of RHO and CDC42 GTPases and Cell Cycle Progression

Cited by 215 publications

References 60 publications

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Cytoskeletal Reorganization Induced by Engagement of the NG2 Proteoglycan Leads to Cell Spreading and Migration

Modulation of Cell-Substrate Adhesion by Arachidonic Acid: Lipoxygenase Regulates Cell Spreading and ERK1/2-inducible Cyclooxygenase Regulates Cell Migration in NIH-3T3 Fibroblasts

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

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