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Vol. 20, Issue 11, 2755-2765, June 1, 2009

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Shear Stress Induced Reorganization of the Keratin Intermediate Filament Network Requires Phosphorylation by Protein Kinase C

Sivaraj Sivaramakrishnan^*, Jaime L. Schneider, Albert Sitikov, Robert D. Goldman, and Karen M. Ridge

Departments of *Biomedical Engineering and Cell and Molecular Biology, and Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL 60611

Submitted October 14, 2008; Revised March 2, 2009; Accepted March 30, 2009
Monitoring Editor: M. Bishr Omary

Keratin intermediate filaments (KIFs) form a fibrous polymer network that helps epithelial cells withstand external mechanical forces. Recently, we established a correlation between the structure of the KIF network and its local mechanical properties in alveolar epithelial cells. Shear stress applied across the cell surface resulted in the structural remodeling of KIF and a substantial increase in the elastic modulus of the network. This study examines the mechanosignaling that regulates the structural remodeling of the KIF network. We report that the shear stress–mediated remodeling of the KIF network is facilitated by a twofold increase in the dynamic exchange rate of KIF subunits, which is regulated in a PKC and 14-3-3–dependent manner. PKC phosphorylates K18pSer33, and this is required for the structural reorganization because the KIF network in A549 cells transfected with a dominant negative PKC , or expressing the K18Ser33Ala mutation, is unchanged. Blocking the shear stress–mediated reorganization results in reduced cellular viability and increased apoptotic levels. These data suggest that shear stress mediates the phosphorylation of K18pSer33, which is required for the reorganization of the KIF network, resulting in changes in mechanical properties of the cell that help maintain the integrity of alveolar epithelial cells.

Address correspondence to: Karen M.. Ridge (kridge{at}northwestern.edu).