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Molecular and Cellular Biology, May 2004, p. 3607-3622, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3607-3622.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Akt2, a Novel Functional Link between p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways in Myogenesis

Ivelisse Gonzalez, Gyanendra Tripathi, Emma J. Carter, Laura J. Cobb, Dervis A. M. Salih, Fiona A. Lovett, Cathy Holding, and Jennifer M Pell*

Signalling Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom

Received 24 June 2003/ Returned for modification 21 August 2003/ Accepted 3 February 2004

Activation of either the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt or the p38 mitogen-activated protein kinase (MAPK) signaling pathways accelerates myogenesis but only when the reciprocal pathway is functional. We therefore examined the hypothesis that cross-activation between these signaling cascades occurs to orchestrate myogenesis. We reveal a novel and reciprocal cross-talk and activation between the PI 3-kinase/Akt and p38 MAPK pathways that is essential for efficient myoblast differentiation. During myoblast differentiation, Akt kinase activity correlated with S473 but not T308 phosphorylation and occurred 24 h after p38 activation. Inhibition or activation of p38 with SB203580, dominant-negative p38, or MKK6EE regulated Akt kinase activity. Analysis of Akt isoforms revealed a specific increase in Akt2 protein levels that coincided with AktS473 phosphorylation during myogenesis and an enrichment of S473-phosphorylated Akt2. Akt2 promoter activity and protein levels were regulated by p38 activation, thus providing a mechanism for communication. Subsequent Akt activation by S473 phosphorylation was PI 3-kinase dependent and specific for Akt2 rather than Akt1. Complementary to p38-mediated transactivation of Akt, activation or inhibition of PI 3-kinase regulated p38 activity upstream of MKK6, demonstrating reciprocal communication and positive feedback characteristic of myogenic regulation. Our findings have identified novel communication between p38 MAPK and PI 3-kinase/Akt via Akt2.

* Corresponding author. Mailing address: The Babraham Institute, Cambridge CB2 4AT, United Kingdom. Phone: 44 1223 496454. Fax: 44 1223 496022. E-mail: jenny.pell{at}bbsrc.ac.uk.

Molecular and Cellular Biology, May 2004, p. 3607-3622, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3607-3622.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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