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© The Rockefeller University Press, 0021-9525/1998//267 $5.00
The Journal of Cell Biology, Volume 143, Number 1, , 1998 267-276

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

Cancer Research Center, The Burnham Institute, La Jolla, California 92037

Adherent cells assemble fibronectin into a fibrillar matrix on their apical surface. The fibril formation is initiated by fibronectin binding to the integrins 5β1 and vβ3, and is completed by a process that includes fibronectin self-assembly. We found that a 76– amino acid fragment of fibronectin (III1-C) that forms one of the self-assembly sites caused disassembly of preformed fibronectin matrix without affecting cell adhesion. Treating attached fibroblasts or endothelial cells with III1-C inhibited cell migration and proliferation. Rho-dependent stress fiber formation and Rho-dependent focal contact protein phosphorylation were also inhibited, whereas Cdc42 was activated, leading to actin polymerization into filopodia. ACK (activated Cdc42-binding kinase) and p38 MAPK (mitogen-activated protein kinase), two downstream effectors of Cdc42, were activated, whereas PAK (p21-activated kinase) and JNK/SAPK (c-Jun NH₂-terminal kinase/ stress-activated protein kinase) were inhibited. III1-C treatment also modulated activation of JNK and ERK (extracellular signal-regulated kinases) in response to growth factors, and reduced the activity of the cyclin E–cdk2 complex. These results indicate that the absence of fibronectin matrix causes activation of Cdc42, and that fibronectin matrix is required for Rho activation and cell cycle progression.

Key Words: extracellular matrix • signal transduction • F-actin • mitogen-activated protein kinase (MAPK) • cyclin E–cdk2

Abbreviations used in this paper: HUVEC, human umbilical vein endothelial cells; LPA, lysophosphatidic acid.

The present address of Sandrine Bourdoulous is Institut Cochin de Génétique Moléculaire, CNRS UPR415, 22 rue Méchain, 75014 Paris, France.

The present address of Gertraud Orend is Friedrich Miescher Institut, Maulbeerstrasse 66, 058 Basel, Switzerland.

The present address of Deidre A. MacKenna is Tanabe Research Laboratories, 4540 Towne Centre Ct., La Jolla, CA 92121.

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