American journal of physiology. Cell physiologyMay 18, 2022

DOCK2 may promote lung scarring by helping lung support cells change into scar-forming cells

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 6, 2026

Abstract

Increased lung DOCK2 expression is associated with pulmonary fibrosis in patients and mouse models.

Transforming growth factor-β (TGF-β) induces DOCK2 expression in both normal and idiopathic pulmonary fibrosis (IPF) human lung fibroblasts.
DOCK2 expression coincides with markers of fibroblast to myofibroblast transition (FMT), such as smooth muscle α-actin, collagen-1, and fibronectin.
Knockdown of DOCK2 reduces TGF-β-induced expression of FMT markers.
The upregulation of DOCK2 by TGF-β is dependent on Smad3 and ERK signaling pathways.
DOCK2 is notably induced in the lungs of IPF patients and in mouse models of pulmonary fibrosis.
DOCK2 deficiency mitigates bleomycin-induced pulmonary fibrosis and α-SMA expression.

Simplified

Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by progressive scarring of the lung. Transforming growth factor-β (TGF-β) signaling plays an essential role in IPF and drives fibroblast to myofibroblast transition (FMT). Dedicator of cytokinesis 2 (DOCK2) is known to regulate diverse immune functions by activating Rac and has been recently implicated in pleural fibrosis. We now report a novel role of DOCK2 in pulmonary fibrosis development by mediating FMT. In primary normal and IPF human lung fibroblasts (HLFs), TGF-β induced DOCK2 expression concurrent with FMT markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-β-induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-β is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-β-mediated induction. TGF-β also stabilized DOCK2 protein, which contributes to increased DOCK2 expression. In addition, DOCK2 was also dramatically induced in the lungs of patients with IPF and in bleomycin, and TGF-β induced pulmonary fibrosis in C57BL/6 mice. Furthermore, increased lung DOCK2 expression colocalized with the FMT marker α-SMA in the bleomycin-induced pulmonary fibrosis model, implicating DOCK2 in the regulation of lung fibroblast phenotypic changes. Importantly, DOCK2 deficiency also attenuated bleomycin-induced pulmonary fibrosis and α-SMA expression. Taken together, our study demonstrates a novel role of DOCK2 in pulmonary fibrosis by modulating FMT and suggests that targeting DOCK2 may present a potential therapeutic strategy for the prevention or treatment of IPF.

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DOCK2 may promote lung scarring by helping lung support cells change into scar-forming cells

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