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Published online 25 December 2000. doi:10.1083/jcb.151.7.1413
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© The Rockefeller University Press, 0021-9525/2000//1413 $5.00
The Journal of Cell Biology, Volume 151, Number 7, , 2000 1413-1422

Original Article

Dual Stimulation of Ras/Mitogen-Activated Protein Kinase and Rhoa by Cell Adhesion to Fibronectin Supports Growth Factor–Stimulated Cell Cycle Progression



Erik H.J. Danena,b, Petra Sonnevelda, Arnoud Sonnenberga, and Kenneth M. Yamadab

a Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
b Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands,(3120) 512-1944(3120) 512-1934

edanen{at}nki.nl

In cellular transformation, activated forms of the small GTPases Ras and RhoA can cooperate to drive cells through the G1 phase of the cell cycle. Here, we show that a similar but substrate-regulated mechanism is involved in the anchorage-dependent proliferation of untransformed NIH-3T3 cells. Among several extracellular matrix components tested, only fibronectin supported growth factor–induced, E2F-dependent S phase entry. Although all substrates supported the mitogen-activated protein kinase (MAPK) response to growth factors, RhoA activity was specifically enhanced on fibronectin. Moreover, induction of cyclin D1 and suppression of p21Cip/Waf occurred specifically, in a Rho-dependent fashion, in cells attached to fibronectin. This ability of fibronectin to stimulate both Ras/MAPK- and RhoA-dependent signaling can explain its potent cooperation with growth factors in the stimulation of cell cycle progression.

Key Words: fibronectin • cell adhesion • G1 cell cycle • integrin • Rho

© 2000 Government

Abbreviations used in this paper: ECM, extracellular matrix; ERK, extracellular signal–regulated kinase; GST, glutathione S-transferase; LPA, lysophosphatidic acid; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase.


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