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J. Biol. Chem., Vol. 282, Issue 23, 17297-17305, June 8, 2007

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AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation^*

Ryan F. L. O'Shaughnessy, Jonathan C. Welti, James C. Cooke, Ariel A. Avilion, Bobby Monks^¶, Morris J. Birnbaum^¶, and Carolyn Byrne¹

From the Centre for Cutaneous Research and Cancer Research UK Skin Tumour Laboratory, Institute of Cell and Molecular Sciences, Barts and the London, Queen Mary University of London, London E1 2AT, United Kingdom and the ^¶University of Pennsylvania School of Medicine and the Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104

AKT activity has been reported in the epidermis associated with keratinocyte survival and differentiation. We show in developing skin that Akt activity associates first with post-proliferative, para-basal keratinocytes and later with terminally differentiated keratinocytes that are forming the fetal stratum corneum. In adult epidermis the dominant Akt activity is in these highly differentiated granular keratinocytes, involved in stratum corneum assembly. Stratum corneum is crucial for protective barrier activity, and its formation involves complex and poorly understood processes such as nuclear dissolution, keratin filament aggregation, and assembly of a multiprotein cell cornified envelope. A key protein in these processes is filaggrin. We show that one target of Akt in granular keratinocytes is HspB1 (heat shock protein 27). Loss of epidermal HspB1 caused hyperkeratinization and misprocessing of filaggrin. Akt-mediated HspB1 phosphorylation promotes a transient interaction with filaggrin and intracellular redistribution of HspB1. This is the first demonstration of a specific interaction between HspB1 and a stratum corneum protein and indicates that HspB1 has chaperone activity during stratum corneum formation. This work demonstrates a new role for Akt in epidermis.

Received for publication, November 7, 2006 , and in revised form, April 5, 2007.

^* This work was supported by Medical Research Council UK Grant CEG, G9803920 (to C. B.), St. Bartholomew's and The London Charitable Fund Fellowship RAB 04/F1 (to R. F. L. O.), and Funds from Cancer Research UK (to C. B.) and was supported in part by National Institutes of Health Grant R01-DK56886 (to M. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Centre for Cutaneous Research, Institute of Cell and Molecular Science, Queen Mary University of London, London E1 2AT, United Kingdom. Tel.: 44-207-882-7165; Fax: 44-207-882-7171; E-mail: c.r.byrne{at}qmul.ac.uk.

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