title: Dual stimulation of Ras/mitogen-activated protein kinase and RhoA by cell adhesion to fibronectin supports growth factor-stimulated cell cycle progression.
abstract: 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.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. edanen@nki.nl
authors.forename: E H
authors.initials: EH
authors.lastname: Danen
authors.forename: P
authors.initials: P
authors.lastname: Sonneveld
authors.forename: A
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: K M
authors.initials: KM
authors.lastname: Yamada
mesh_terms: 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*
chemical_list: 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