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Molecular and Cellular Biology, February 2004, p. 1505-1515, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1505-1515.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Kinase B/Akt Acts via Glycogen Synthase Kinase 3 To Regulate Recycling of {alpha}vß3 and {alpha}5ß1 Integrins

Marnie S. Roberts,1,{dagger} Alison J. Woods,1 Trevor C. Dale,2 Peter van der Sluijs,3 and Jim C. Norman1*

Department of Biochemistry, University of Leicester, Leicester LE1 7RH,1 Cardiff School of Biosciences, Cardiff CF10 3US, United Kingdom,2 Department of Cell Biology, Utrecht University School of Medicine, 3584 CX Utrecht, The Netherlands3

Received 14 April 2003/ Returned for modification 19 May 2003/ Accepted 3 November 2003

Protein kinase B (PKB)/Akt is known to promote cell migration, and this may contribute to the enhanced invasiveness of malignant cells. To elucidate potential mechanisms by which PKB/Akt promotes the migration phenotype, we have investigated its role in the endosomal transport and recycling of integrins. Whereas the internalization of {alpha}vß3 and {alpha}5ß1 integrins and their transport to the recycling compartment were independent of PKB/Akt, the return of these integrins (but not internalized transferrin) to the plasma membrane was regulated by phosphatidylinositol 3-kinases and PKB/Akt. The blockade of integrin recycling and cell spreading on integrin ligands effected by inhibition of PKB/Akt was reversed by inhibition of glycogen synthase kinase 3 (GSK-3). Moreover, expression of nonphosphorylatable active GSK-3ß mutant GSK-3ß-A9 suppressed recycling of {alpha}5ß1 and {alpha}vß3 and reduced cell spreading on ligands for these integrins, indicating that PKB/Akt promotes integrin recycling by phosphorylating and inactivating GSK-3. We propose that the ability of PKB/Akt to act via GSK-3 to promote the recycling of matrix receptors represents a key mechanism whereby integrin function and cell migration can be regulated by growth factors.

* Corresponding author. Mailing address: Department of Biochemistry, University of Leicester, University Rd., Leicester LE1 7RH, United Kingdom. Phone: 0116-252-5250. Fax: 0116-252-3369. E-mail: jcn2{at}le.ac.uk.

{dagger} Present address: MRC Laboratory for Molecular Cell Biology, Cell Biology Unit, University College London, WC1E 6BT London, United Kingdom.

Molecular and Cellular Biology, February 2004, p. 1505-1515, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1505-1515.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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