Rafeul Alam

Unc119 Regulates Myofibroblast Differentiation through the Activation of Fyn and the p38 MAPK Pathway

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 α-smooth muscle actin (α-SMA) and myofibroblast differentiation by TGF-β 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-β 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 α-SMA in SYF cells and this defect is restored upon reconstitution with Fyn indicating that Unc119 stimulation of α-SMA requires at least Fyn. Unc119 overexpression stimulated p38, but not JNK, phosphorylation. Blocking p38 MAPK resulted in reduced α-SMA expression by Unc119 suggesting that the p38 pathway regulates Unc119-induced myofibroblast differentiation. Unc119 stimulates the production of TGF-β 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 α-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 signaling mechanism of eosinophil activation

Eosinophils play an important role in certain aspects of asthma pathogenesis. This review focuses on the mechanism of activation of eosinophils by the growth factor interleukin-5 and the CC chemokine receptor-3. Interleukin-5 activates members of the Janus and Src family of kinases. The latter kinases are largely responsible for the generation of initial signaling events. CC chemokine receptor-3, in contrast, signals through heterotrimeric G-proteins. Subsequently, various signaling pathways are activated, which converge on four major pathways – the mitogen-activated protein kinase pathway, the phosphoinositide-3 kinase pathway, the calcium signaling pathway and the Janus–signal transducer and activator of transcription signaling pathway. The biologic consequences of many of these signaling pathways are also discussed.