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National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206
Unc119 is an adaptor protein that is involved in the development of the vertebrate nervous system. We have shown that Unc119 stimulates the induction of 
-smooth muscle actin (-SMA) and myofibroblast differentiation by TGF-
in human lung fibroblasts. Unc119 increases the kinase activity of Fyn and associates with it in coprecipitation and colocalization studies. Phosphorylation and activation of Fyn in response to TGF- and platelet-derived growth factor is delayed in Unc119-deficient cells. This delay translates into suppressed cell proliferation. In Src family kinase-deficient (SYF) cells, Unc119 knockdown does not affect cell proliferation. The result suggests that Unc119 interacts with Fyn in the early stages of signal generation and its presence is essential for conducive signal transduction. Unc119 overexpression does not stimulate -SMA in SYF cells and this defect is restored upon reconstitution with Fyn indicating that Unc119 stimulation of -SMA requires at least Fyn. Unc119 overexpression stimulated p38, but not JNK, phosphorylation. Blocking p38 MAPK resulted in reduced -SMA expression by Unc119 suggesting that the p38 pathway regulates Unc119-induced myofibroblast differentiation. Unc119 stimulates the production of TGF- and IL-6, known inducers of myofibroblast differentiation. Thus, Unc119 regulates receptor-mediated signal transduction and myofibroblast differentiation by activating Fyn and the p38 MAPK pathway. Using primary lung fibroblasts from patients with fibrotic lung diseases and control subjects, we show that the expression of -smooth muscle actin is highly correlated with that of Unc119. Taken together, our results suggest that Unc119 plays an important role in fibrotic processes through myofibroblast differentiation.
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.
1 This work was supported by National Institutes of Health Grants RO1 AI50179, AI059719, and AI68088.
2 Address correspondence and reprint requests to Dr. Rafeul Alam, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: alamr{at}njrc.org
3 Abbreviations used in this paper: PDGF, platelet-derived growth factor; SFK, Src family kinase; -SMA, -smooth muscle actin; RV, retroviral vector; SH, Src homology; EGF, epidermal growth factor; siRNA, small interfering RNA.
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