PI3-kinase p110 alpha mediates beta 1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading
2010 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, no 12, 1838-1848 p.Article in journal (Refereed) Published
Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in beta 1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane substrate interface demonstrated that beta 1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10 min. This process required actin polymerization and involved activation of PI3K. Isoform-selective pharmacological inhibition identified p110 alpha as the PI3K catalytic isoform mediating both beta 1 integrin-induced cell spreading and Akt phosphorylation. A K756L mutation in the membrane-proximal part of the beta 1 integrin subunit, known to cause impaired Akt phosphorylation after integrin stimulation, induced slower cell spreading. The initial beta 1 integrin-regulated cell spreading as well as Akt phosphorylation were sensitive to the tyrosine kinase inhibitor PP2, but were not dependent on Src family kinases, FAK or EGF/PDGF receptor transactivation. Notably, cells expressing a Ras binding-deficient p110 alpha mutant were severely defective in integrin-induced Akt phosphorylation, but exhibited identical membrane spreading kinetics as wild-type p110 alpha cells. We conclude that p110 alpha mediates beta 1 integrin-regulated activation of Akt and actin polymerization important for survival and lamellipodia dynamics. This could contribute to the tumorigenic properties of cells expressing constitutively active p110 alpha.
Place, publisher, year, edition, pages
2010. Vol. 22, no 12, 1838-1848 p.
beta 1 integrin, PI3K, p110 alpha, Cell spreading, Akt
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-134169DOI: 10.1016/j.cellsig.2010.07.011ISI: 000282857200006OAI: oai:DiVA.org:uu-134169DiVA: diva2:371816
Correction in: Cellular signaling, vol. 24, issue 4, p: 971-972, DOI: 10.1016/j.cellsig.2011.12.0102010-11-222010-11-222012-04-19Bibliographically approved