title: Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is critical for formation of α-smooth muscle actin filaments during myofibroblast differentiation.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Cai
authors.forename: Chu-Fang
authors.initials: CF
authors.lastname: Chou
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.forename: Anni
authors.initials: A
authors.lastname: Zheng
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.forename: Haotian
authors.initials: H
authors.lastname: Fang
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Luckhardt
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D051378:Actin-Related Protein 3 / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*
chemical_list: D051378:Actin-Related Protein 3; D000199:Actins; C495929:Actr3 protein, mouse; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C544013:alpha-smooth muscle actin, mouse; D014443:Tyrosine; D003094:Collagen; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse