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A more recent version of this article appeared on June 1, 2002
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Submitted on December 21, 2001
Revised on March 4, 2002
Accepted on March 6, 2002
1 Department of Medicine, VA Palo Alto Health Care System, 3801 Miranda Avenue, Mail code 154J, Palo Alto, CA 94304, USA; and the Digestive Disease Center, Stanford University School of Medicine
2 Department of Chemical Biology, Universite du Quebec a Trois-Rivieres, Canada
* Corresponding author. E-mail address: mbishr{at}stanford.edu.
Epithelial cell keratins make up the type-I (K9-K20) and type-II (K1-K8) intermediate filament proteins. In glandular epithelia, K8 becomes phosphorylated on S73 (71LLpSPL) in cultured cells and tissues during stress, apoptosis and, mitosis. Of all known proteins, the context of the K8 S73 motif (LLS/TPL) is unique to type-II keratins and is conserved in epidermal K5/K6, esophageal K4 and type II hair keratins, except that serine is replaced by threonine. Since knowledge regarding epidermal and esophageal keratin regulation is limited, we tested if K4-K6 are phosphorylated on the LLTPL motif. K5 and K6 become phosphorylated in vitro on threonine by the stress-activated kinase p38. Site-specific anti-phosphokeratin antibodies to LLpTPL were generated, which demonstrated negligible basal K4-K6 phosphorylation. In contrast, treatment of primary keratinocytes and other cultured cells, and ex vivo skin and esophagus cultures, with serine/threonine phosphatase inhibitors causes a dramatic increase in K4-K6 LLpTPL phosphorylation. This phosphorylation is accompanied by keratin solubilization, filament reorganization and collapse. K5/K6 LLTPL phosphorylation occurs in vivo during mitosis and apoptosis induced by ultraviolet light or anisomycin, and in human psoriatic skin and squamous cell carcinoma. In conclusion, type-II keratins of proliferating epithelia undergo phosphorylation at a unique and conserved motif as part of physiologic mitotic and stress-related signals.
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