The adaptor protein Shc couples a class of integrins to the control of cell cycle progression.
We provide evidence that a class of integrins combines with the adaptor Shc and thereby with Grb2. Coimmunoprecipitation and mutagenesis experiments indicate that the recruitment of Shc is specified by the extracellular or transmembrane domain of integrin alpha subunit and suggest that this process is mediated by caveolin. Mutagenesis and dominant-negative inhibition studies reveal that Shc is necessary and sufficient for activation of the MAP kinase pathway in response to integrin ligation. Mitogens and Shc-activating integrins cooperate to promote transcription from the Fos serum response element and transit through G1. In contrast, adhesion mediated by integrins not linked to Shc results in cell cycle arrest and apoptosis even in presence of mitogens. These findings indicate that the association of specific integrins with Shc regulates cell survival and cell cycle progression.
Wary
K K
KK
Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
Mainiero
F
F
Isakoff
S J
SJ
Marcantonio
E E
EE
Giancotti
F G
FG
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D039564:Integrin alphaV; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D026362:Serum Response Factor; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D039564:Integrin alphaV; D019012:Integrin beta1; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; D026362:Serum Response Factor; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases