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

• Published in: The Journal of biological chemistry Vol. 280; no. 14; pp. 13879 - 13887
• Main Authors: Tourkina, Elena, Gooz, Pal, Pannu, Jaspreet, Bonner, Michael, Scholz, Dimitri, Hacker, Sharon, Silver, Richard M., Trojanowska, Maria, Hoffman, Stanley
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 08.04.2005
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M412551200

The roles of MEK, ERK, the ϵ and α 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 PKCϵ leads to MEK/ERK activation. In another, increased PKCα 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 PKCϵ, PKCα, 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, PKCϵ, PKCα, and caveolin-1 regulates collagen expression in normal lung tissue and is perturbed during fibrosis.