Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle.
Adhesion to fibronectin through the alpha5beta1 integrin enables endothelial cells to proliferate in response to growth factors, whereas adhesion to laminin through alpha2beta1 results in growth arrest under the same conditions. On laminin, endothelial cells fail to translate Cyclin D1 mRNA and activate CDK4 and CDK6. Activated Rac, but not MEK1, PI-3K, or Akt, rescues biosynthesis of cyclin D1 and progression through the G(1) phase. Conversely, dominant negative Rac prevents these events on fibronectin. Mitogens promote activation of Rac on fibronectin but not laminin. This process is mediated by SOS and PI-3K and requires coordinate upstream signals through Shc and FAK. These results indicate that Rac is a crucial mediator of the integrin-specific control of cell cycle in endothelial cells.
Mettouchi
A
A
Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Klein
S
S
Guo
W
W
Lopez-Lago
M
M
Lemichez
E
E
Westwick
J K
JK
Giancotti
F G
FG
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015152:Blotting, Northern; D042846:CDC2-CDC28 Kinases; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D042846:CDC2-CDC28 Kinases; D051242:Caveolin 1; D022461:Caveolins; D016895:Culture Media, Serum-Free; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D005353:Fibronectins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007328:Insulin; D016023:Integrins; D007797:Laminin; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin; D011993:Recombinant Fusion Proteins; D020837:SOS1 Protein; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020744:rac GTP-Binding Proteins; C528024:SHC1 protein, human; C121346:laminin 1; C496050:PTK2 protein, human; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human