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(Received for publication, August 12, 1996, and in revised form, January 10, 1997)
From the Department of Medicine, Veterans Administration Palo Alto
Health Care System, Palo Alto, California 94304, and the Digestive
Disease Center, Stanford University School of Medicine,
Stanford, California 94305-5487
Dynamic phosphorylation is one mechanism that
regulates the more than 20 keratin type I and II intermediate filament
proteins in epithelial cells. The major type II keratin in "simple
type" glandular epithelia is keratin 8 (K8). We used biochemical and mutational approaches to localize two major in vivo
phosphorylation sites of human K8 to the head (Ser-23) and tail
(Ser-431) domains. Since Ser-23 of K8 is highly conserved among all
type II keratins, we also examined if the corresponding Ser-59 in
stratified epithelial keratin 6e is phosphorylated. Mutation of K6e
Ser-59 abolished its phosphorylation in
32PO4-labeled baby hamster kidney cell
transfectants. With regard to K8 phosphorylation at Ser-431, it
increases dramatically upon stimulation of cells with epidermal growth
factor (EGF) or after mitotic arrest and is the major K8 phosphorylated
residue after incubating K8 immunoprecipitates with mitogen-activated
protein or cdc2 kinases. A monoclonal antibody that specifically
recognizes phosphoserine 431-K8 manifests increased reactivity with K8
and recognizes reorganized K8/18 filaments after EGF stimulation. Our
results suggest that in vivo serine phosphorylation of K8 and K6e within the conserved head domain motif is likely to reflect a
conserved phosphorylation site of most if not all type II keratins. Furthermore, K8 Ser-431 phosphorylation occurs after EGF stimulation and during mitotic arrest and is likely to be mediated by
mitogen-activated protein and cdc2 kinases, respectively.
Volume 272, Number 11,
Issue of March 14, 1997
pp. 7556-7564
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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