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

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...

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Bibliographic Details
Published in:The Journal of cell biology 2000-12, Vol.151 (7), p.1413-1422
Main Authors: Erik H. J. Danen, Sonneveld, Petra, Sonnenberg, Arnoud, Yamada, Kenneth M.
Format: Article
Language:English
Subjects:
3T3 Cells
Actins - metabolism
Animals
B lymphocytes
Carrier Proteins
Cell Adhesion
Cell cycle
Cell Cycle - drug effects
Cell Cycle Proteins
Cell growth
Cells
Culture Media, Serum-Free
Cyclin D1 - genetics
Cyclin D1 - metabolism
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Cyclins - antagonists & inhibitors
Cyclins - genetics
Cyclins - metabolism
Cytoskeleton - metabolism
DNA-Binding Proteins
E2F Transcription Factors
Enzyme Activation
Fibronectins - metabolism
G1 Phase
Gene expression regulation
Growth Substances - pharmacology
Integrins
Interphase
Mice
Mitogen-Activated Protein Kinases - metabolism
Models, Biological
NIH 3T3 cells
Original
ras GTPase-Activating Proteins - metabolism
Retinoblastoma Protein - metabolism
Retinoblastoma-Binding Protein 1
rhoA GTP-Binding Protein - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
S Phase
Signal Transduction - drug effects
Transcription Factor DP1
Transcription Factors - metabolism
Transfection
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Summary: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/Wafoccurred 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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.151.7.1413