EGFR and beta1 integrins utilize different signaling pathways to activate Akt.
Akt, also called PKB, is a serine/threonine kinase that plays a major role in cell survival. It can be activated by several cellular receptors, including integrins and growth factor receptors, in PI3K-dependent manners. In this study, we analyzed the two current models for Akt activation upon beta1 integrin-mediated adhesion: via focal adhesion kinase and via transactivation of the EGF receptor. Distinct differences in the pathways leading to phosphorylation and activation of Akt from stimulated beta1 integrins and EGF receptor were observed, including opposing sensitivity to the tyrosine kinase inhibitors PP2 and Gefitinib. Using knockout cells and integrin mutant cells, we show that beta1 integrins can induce phosphorylation of Akt at Ser473 and Thr308 and Akt kinase activity independently of the EGF receptor activity, focal adhesion kinase, and the Src family members. In contrast to stimulation with EGF, beta1 integrin-mediated adhesion did not induce Akt tyrosine phosphorylation. Moreover, tyrosine phosphorylation of Akt was found not to be required for its catalytic activity. The results identify a previously unrecognized mechanism by which beta1 integrins activate the PI3K/Akt pathway.
Velling
Teet
T
Department of Medical Sciences, University Hospital, 75185, Uppsala, Sweden. Teet.Velling@medsci.uu.se
Stefansson
Anne
A
Johansson
Staffan
S
D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000235:genetics / Q000378:metabolism
D019012:Integrin beta1; D013912:Threonine; D012694:Serine; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt