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M107623200v1
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Papers In Press, published online ahead of print January 11, 2002
J. Biol. Chem, 10.1074/jbc.M107623200
Submitted on August 9, 2001
Revised on January 11, 2002
Accepted on January 10, 2002

Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease-causing mutation

Nam-On Ku, Salman Azhar, and M. Bishr Omary

Medicine, Palo Alto VA Medical Center, Palo Alto, CA 94304

Corresponding Author: mbishr{at}stanford.edu

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 Ser73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. In cells, Ser73 phosphorylation occurs in association with p38 kinase activation, and is inhibited by SB203580 but not by PD98059. Transfection of K8 Ser73{arrow}Ala or K8 Ser73{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 Ser73{arrow}Asp K8, while Ser73{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 Leu159{arrow}Pro (156NQSLLQPL{arrow}156NQSPLQPL) leads to epidermolytic hyperkeratosis, we tested and showed that the analogous K8 Leu71{arrow}Pro leads to K8 hyperphosphorylation by p38 kinase and in transfected cells, likely due to Ser70 neo-phosphorylation, in association with significant keratin filament collapse upon cell exposure to okadaic acid. Hence, K8 Ser73 is a physiologic phosphorylation site for p38 kinase, and its phosphorylation plays an important role in keratin filament reorganization. The Ser73{arrow}Ala-associated filament-reorganization defect is rescued by a Ser73{arrow}Asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.


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