The coupling of alpha6beta4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation.
The signaling pathways linking integrins to nuclear events are incompletely understood. We have examined intracellular signaling by the alpha6beta4 integrin, a laminin receptor expressed in basal keratinocytes and other cells. Ligation of alpha6beta4 in primary human keratinocytes caused tyrosine phosphorylation of Shc, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. In contrast, ligation of the laminin- and collagen-binding integrins alpha3beta1 and alpha2beta1 did not cause these events. While the stimulation of Erk by alpha6beta4 was suppressed by dominant-negative Shc, Ras and RhoA, the activation of Jnk was inhibited by dominant-negative Ras and Rac1 and by the phosphoinositide 3-kinase inhibitor Wortmannin. Adhesion mediated by alpha6beta4 induced transcription from the Fos serum response element and promoted cell cycle progression in response to mitogens. In contrast, alpha3beta1- and alpha2beta1-dependent adhesion did not induce these events. These findings suggest that the coupling of alpha6beta4 integrin to the control of cell cycle progression mediated by Shc regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.
Mainiero
F
F
Department of Pathology, New York University School of Medicine, New York 10016, USA.
Murgia
C
C
Wary
K K
KK
Curatola
A M
AM
Pepe
A
A
Blumemberg
M
M
Westwick
J K
JK
Der
C J
CJ
Giancotti
F G
FG
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002448:Cell Adhesion; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D051380:GRB2 Adaptor Protein; D017781:Genes, Immediate-Early; D006367:HeLa Cells; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology*; D007797:Laminin / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D026362:Serum Response Factor; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D000939:Epitopes; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051380:GRB2 Adaptor Protein; D039161:Integrin alpha6beta4; D016023:Integrins; D007797:Laminin; D020930:MAP Kinase Kinase Kinases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D026362:Serum Response Factor; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C528024:SHC1 protein, human; C528034:Shc1 protein, mouse; C089319:Ras-dependent mitogen-activated protein kinase kinase kinase