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 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 p21(Cip/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.
Danen
E H
EH
Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. edanen@nki.nl
Sonneveld
P
P
Sonnenberg
A
A
Yamada
K M
KM
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D002448:Cell Adhesion; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism*; D016193:G1 Phase; D006133:Growth Substances / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005353:Fibronectins; D006133:Growth Substances; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein