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EGFR and β1-Integrins utilise different signalling pathways to activate Akt
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2008 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 314, no 2, 309-316 p.Article in journal (Refereed) Published
Abstract [en]

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 β1 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 β1 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 β1 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, β1 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 β1 integrins activate the PI3K/Akt pathway.

Place, publisher, year, edition, pages
2008. Vol. 314, no 2, 309-316 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96243DOI: 10.1016/j.yexcr.2007.08.018OAI: oai:DiVA.org:uu-96243DiVA: diva2:170750
Available from: 2007-10-11 Created: 2007-10-11 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mechanisms of Integrin Signal Transduction
Open this publication in new window or tab >>Mechanisms of Integrin Signal Transduction
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Integrins are a protein family of cell surface receptors, expressed in all cell types in the human body, except the red blood cells. Besides their importance in mediating physical connections with the surrounding environment, the integrin family members are also vital signalling mediators. They have no intrinsic kinase activity; instead the signals are transduced through conformational changes.

In this thesis, work is presented which is focused on molecular mechanisms of integrin signal transduction. The signal transduction was first studied from a structural point of view, determining the transmembrane domain borders of a few selected integrin family members and ruling out a signalling model involving a “piston-like” movement.

Then, downstream signalling events involved in the beta1 integrin-induced activation of Akt via the PI3kinase family were characterized. Our results identify a novel pathway for PI3K/Akt activation by beta1 integrins, which is independent of focal adhesion kinase (FAK), Src and EGF receptor. Furthermore, both beta1 integrins and EGF receptors induced phosphorylation of Akt at the regulatory sites Thr308 and Ser473, but only EGF receptor stimulation induced tyrosine phosphorylation of Akt.

Finally, signals from beta1 integrins underlying the morphologic changes during cell spreading were studied. A rapid integrin-induced cell spreading dependent on actin polymerisation was observed by using total internal reflection fluorescence (TIRF) microscopy. This integrin-induced actin polymerisation was shown to be dependent on PI3K p110alpha catalytic subunit and to involve the conserved Lys756 in the beta1-integrin membrane proximal part.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 275
Keyword
Cell biology, Integrin, Integrin signalling, PI3K, Akt/PKB, Integrin transmembrane domain, cell spreading, Cellbiologi
Identifiers
urn:nbn:se:uu:diva-8221 (URN)978-91-554-6974-0 (ISBN)
Public defence
2007-10-19, B42, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-10-11 Created: 2007-10-11Bibliographically approved

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Johansson, Staffan

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