PubMed Journals: J Biol Chem
Source: PMID: 11788583
⇦ ⇨ J Biol Chem. 2002 Mar 29;277(13):10775-82.
⇩ Epub 2002 Jan 11.
Keratin 8 phosphorylation by p38 kinase
regulates cellular keratin filament reorganization:
modulation by a keratin 1-like disease causing
Ku NO(1), Azhar S, Omary MB.
(1) Department of Medicine, and Geriatric
Research, Education and Clinical Center,
Veterans Affairs Palo Alto Health Care System,
Palo Alto, California 94304, USA.
Keratin 8 (K8) serine 73 occurs within
a relatively conserved type II keratin motif
((68)NQSLLSPL) 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 --> 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 ((157)NQSLLQPL --> (157)NQSPLQPL)
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.
DOI: 10.1074/jbc.M107623200 PMID: 11788583
[Indexed for MEDLINE]