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Originally published In Press as doi:10.1074/jbc.M107623200 on January 11, 2002

J. Biol. Chem., Vol. 277, Issue 13, 10775-10782, March 29, 2002
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Keratin 8 Phosphorylation by p38 Kinase Regulates Cellular Keratin Filament Reorganization
MODULATION BY A KERATIN 1-LIKE DISEASE-CAUSING MUTATION*

Nam-On KuDagger , Salman Azhar, and M. Bishr Omary§

From the Department of Medicine, and  Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304 and the Digestive Disease Center, Stanford University School of Medicine, Stanford, California 94305

Keratin 8 (K8) serine 73 occurs within a relatively conserved type II keratin motif (68NQSLLSPL) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that Ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. In cells, Ser-73 phosphorylation occurs in association with p38 kinase activation and is inhibited by SB203580 but not by PD98059. Transfection of K8 Ser-73 right-arrow Ala or K8 Ser-73 right-arrow Asp with K18 generates normal-appearing filaments. In contrast, exposure to okadaic acid results in keratin filament destabilization in cells expressing wild-type or Ser-73 right-arrow Asp K8, whereas Ser-73 right-arrow Ala K8-expressing cells maintain relatively stable filaments. p38 kinase associates with K8/18 immunoprecipitates and binds selectively with K8 using an in vitro overlay assay. Given that K1 Leu-160 right-arrow Pro (157NQSLLQPL right-arrow 157NQSPLQPL) leads to epidermolytic hyperkeratosis, we tested and showed that the analogous K8 Leu-71 right-arrow Pro leads to K8 hyperphosphorylation by p38 kinase in vitro and in transfected cells, likely due to Ser-70 neo-phosphorylation, in association with significant keratin filament collapse upon cell exposure to okadaic acid. Hence, K8 Ser-73 is a physiologic phosphorylation site for p38 kinase, and its phosphorylation plays an important role in keratin filament reorganization. The Ser-73 right-arrow Ala-associated filament reorganization defect is rescued by a Ser-73 right-arrow Asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

* This work was supported by National Institutes of Health Grant DK52951 and Digestive Disease Center Grant DK56339 and by a Department of Veterans Affairs Career Development award.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom reprint requests should be addressed.

§ To whom correspondence should be addressed: Palo Alto Veterans Affairs Medical Center, 3801 Miranda Ave., 154J, Palo Alto, CA 94304.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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