Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of α-smooth muscle actin filaments during myofibroblast differentiation.

Guo-Qiang Cai, Chu-Fang Chou, Meng Hu, Anni Zheng, Louis F Reichardt, Jun-Lin Guan, Haotian Fang, Tracy R Luckhardt, Yong Zhou, Victor J Thannickal, Qiang Ding

American journal of physiology. Lung cellular and molecular physiology 2012 Oct 15

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Myofibroblasts are implicated in pathological stromal responses associated with lung fibrosis. One prominent phenotypic marker of fully differentiated myofibroblasts is the polymerized, thick cytoplasmic filaments containing newly synthesized α-smooth muscle actin (α-SMA). These α-SMA-containing cytoplasmic filaments are important for myofibroblast contractility during tissue remodeling. However, the molecular mechanisms regulating the formation and maturation of α-SMA-containing filaments have not been defined. This study demonstrates a critical role for neuronal Wiskott-Aldrich syndrome protein (N-WASP) in regulating the formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and in myofibroblast contractility. Focal adhesion kinase (FAK) is activated by transforming growth factor-β1 (TGF-β1) and is required for phosphorylation of tyrosine residue 256 (Y256) of N-WASP. Phosphorylation of Y256 of N-WASP is essential for TGF-β1-induced formation of α-SMA-containing cytoplasmic filaments in primary human lung fibroblasts. In addition, we demonstrate that actin-related protein (Arp) 2/3 complex is downstream of N-WASP and mediates the maturation of α-SMA-containing cytoplasmic filaments. Together, this study supports a critical role of N-WASP in integrating FAK and Arp2/3 signaling to mediate formation of α-SMA-containing cytoplasmic filaments during myofibroblast differentiation and maturation.

Citation

Guo-Qiang Cai, Chu-Fang Chou, Meng Hu, Anni Zheng, Louis F Reichardt, Jun-Lin Guan, Haotian Fang, Tracy R Luckhardt, Yong Zhou, Victor J Thannickal, Qiang Ding. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of α-smooth muscle actin filaments during myofibroblast differentiation. American journal of physiology. Lung cellular and molecular physiology. 2012 Oct 15;303(8):L692-702