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J. Biol. Chem., Vol. 277, Issue 13, 10775-10782, March 29, 2002
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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
Keratin 8 Phosphorylation by p38 Kinase Regulates Cellular
Keratin Filament Reorganization
MODULATION BY A KERATIN 1-LIKE DISEASE-CAUSING MUTATION*
,
Ala or K8
Ser-73 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 Asp K8,
whereas Ser-73 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 Pro (157NQSLLQPL 157NQSPLQPL) leads to epidermolytic hyperkeratosis, we
tested and showed that the analogous K8 Leu-71 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 Ala-associated filament reorganization defect is rescued by a Ser-73
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.
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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