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J. Biol. Chem., Vol. 280, Issue 14, 13879-13887, April 8, 2005

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Opposing Effects of Protein Kinase C and Protein Kinase C on Collagen Expression by Human Lung Fibroblasts Are Mediated via MEK/ERK and Caveolin-1 Signaling^*

Elena Tourkina, Pal Gooz, Jaspreet Pannu, Michael Bonner, Dimitri Scholz¶, Sharon Hacker||, Richard M. Silver, Maria Trojanowska, and Stanley Hoffman

From the Division of Rheumatology and Immunology and the ^¶Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and the ^||Department of Biology, The Citadel, Charleston, South Carolina 29409

The roles of MEK, ERK, the and isoforms of protein kinase C (PKC), and caveolin-1 in regulating collagen expression were studied in normal lung fibroblasts. Knocking down caveolin-1 gave particularly striking results. A 70% decrease caused a 5-fold increase in MEK/ERK activation and collagen expression. The combined data reveal a branched signaling pathway. In its central portion MEK activates ERK, leading to increased collagen expression. Two branches converge on MEK/ERK. In one, increased PKC leads to MEK/ERK activation. In another, increased PKC induces caveolin-1 expression, which in turn inhibits MEK/ERK activation and collagen expression. Lung fibroblasts from scleroderma patients with pulmonary fibrosis showed altered signaling. Consistent with their overexpression of collagen, scleroderma lung fibroblasts contain more activated MEK/ERK and less caveolin-1 than normal lung fibroblasts. Because cutaneous fibrosis is the hallmark of scleroderma, we also studied dermal fibroblasts. As in lung, there was more activated MEK/ERK in cells from scleroderma patients than in control cells, and MEK inhibition decreased collagen expression. However, the distinctive levels of PKC, PKC, and caveolin-1 in lung and dermal fibroblasts from scleroderma patients and control subjects indicate that the links between these signaling proteins and MEK/ERK must function differently in the four cell types. Finally, we confirmed the relevance of these signaling cascades in vivo. The combined results demonstrate that a branched signaling pathway involving MEK, ERK, PKC, PKC, and caveolin-1 regulates collagen expression in normal lung tissue and is perturbed during fibrosis.

Received for publication, November 5, 2004 , and in revised form, January 25, 2005.

^* This work was supported by a grant from the Scleroderma Federation (to E. T.) and by Grant P60 AR049459 (to R. M. S.) from the United States Public Heath Service, Grant R01 AR44883 (to M. T.) from NIAMS, National Institutes of Health, Grant R21 AT00382 from the National Center for Complementary and Alternative Medicine (to S. H.), and Grant R01 HL73718 from the NHLBI, National Institutes of Health (to S. H.). 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.

To whom correspondence should be addressed: Division of Rheumatology and Immunology, Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-3487; Fax: 843-792-7121; E-mail: tourkine{at}musc.edu.

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