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J. Biol. Chem., Vol. 280, Issue 34, 30400-30405, August 26, 2005

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Keratin 8 Phosphorylation by Protein Kinase C Regulates Shear Stress-mediated Disassembly of Keratin Intermediate Filaments in Alveolar Epithelial Cells^*

Karen M. Ridge¶||, Laura Linz, Frederick W. Flitney, Edward R. Kuczmarski, Ying-Hao Chou, M. Bishr Omary**, Jacob Iasha Sznajder, and Robert D. Goldman

From the Division of Pulmonary and Critical Care Medicine and the Department of Cell Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611 and the ^¶Medical Service, Veteran Affairs Chicago Health Care System Chicago, Illinois 60611

Phosphorylation of keratin intermediate filaments (IF) is known to affect their assembly state and organization; however, little is known about the mechanisms regulating keratin phosphorylation. In this study, we demonstrate that shear stress, but not stretch, causes disassembly of keratin IF in lung alveolar epithelial cells (AEC) and that this disassembly is regulated by protein kinase C -mediated phosphorylation of keratin 8 (K8) Ser-73. Specifically, in AEC subjected to shear stress, keratin IF are disassembled, as reflected by their increased solubility. In contrast, AEC subjected to stretch showed no changes in the state of assembly of IF. Pretreatment with the protein kinase C (PKC) inhibitor, bisindolymaleimide, prevents the increase in solubility of either K8 or its assembly partner K18 in shear-stressed AEC. Phosphoserine-specific antibodies demonstrate that K8 Ser-73 is phosphorylated in a time-dependent manner in shear-stressed AEC. Furthermore, we showed that shear stress activates PKC and that the PKC peptide antagonist, V1-1, significantly attenuates the shear stress-induced increase in keratin phosphorylation and solubility. These data suggested that shear stress mediates the phosphorylation of serine residues in K8, leading to the disassembly of IF in alveolar epithelial cells. Importantly, these data provided clues regarding a molecular link between mechanically induced signal transduction and alterations in cytoskeletal IF.

Received for publication, April 19, 2005 , and in revised form, June 3, 2005.

^* This work was supported by grants from the National Institutes of Health (Grant NHLBI P01-HL71643 and NIH-NIDR Grant PO1-DE 12328), the Francis Foundation (the Parker B. Francis Fellowship to K. M. R.), and the Department of Veteran Affairs (the VA-MREP to K. M. R.) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Dept. of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304.

^|| To whom correspondence should be addressed: Northwestern University Medical School, Pulmonary and Critical Care Medicine, 240 East Huron, McGaw 2328, Chicago, IL 60611. Tel.: 312-503-1648; Fax: 312-908-4650; E-mail: kridge{at}northwestern.edu.

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