{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T05:13:32Z","timestamp":1785042812182,"version":"3.55.0"},"reference-count":50,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2016,5,29]],"date-time":"2016-05-29T00:00:00Z","timestamp":1464480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In airway smooth muscle, tension development caused by a contractile stimulus requires phosphorylation of the 20\u00a0kDa myosin light chain (MLC), which activates crossbridge cycling and the polymerization of a pool of submembraneous actin.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The p21\u2010activated kinases (Paks) can regulate the contractility of smooth muscle and non\u2010muscle cells, and there is evidence that this occurs through the regulation of MLC phosphorylation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We show that Pak has no effect on MLC phosphorylation during the contraction of airway smooth muscle, and that it regulates contraction by mediating actin polymerization.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We find that Pak phosphorylates the adhesion junction protein, paxillin, on Ser273, which promotes the formation of a signalling complex that activates the small GTPase, cdc42, and the actin polymerization catalyst, neuronal Wiskott\u2013Aldrich syndrome protein (N\u2010WASP).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These studies demonstrate a novel role for Pak in regulating the contractility of smooth muscle by regulating actin polymerization.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The p21\u2010activated kinases (Pak) can regulate contractility in smooth muscle and other cell and tissue types, but the mechanisms by which Paks regulate cell contractility are unclear. In airway smooth muscle, stimulus\u2010induced contraction requires phosphorylation of the 20\u00a0kDa light chain of myosin, which activates crossbridge cycling, as well as the polymerization of a small pool of actin. The role of Pak in airway smooth muscle contraction was evaluated by inhibiting acetylcholine (ACh)\u2010induced Pak activation through the expression of a kinase inactive mutant, Pak1 K299R, or by treating tissues with the Pak inhibitor, IPA3. Pak inhibition suppressed actin polymerization and contraction in response to ACh, but it did not affect myosin light chain phosphorylation. Pak activation induced paxillin phosphorylation on Ser273; the paxillin mutant, paxillin S273A, inhibited paxillin Ser273 phosphorylation and inhibited actin polymerization and contraction. Immunoprecipitation analysis of tissue extracts and proximity ligation assays in dissociated cells showed that Pak activation and paxillin Ser273 phosphorylation triggered the formation of an adhesion junction signalling complex with paxillin that included G\u2010protein\u2010coupled receptor kinase\u2010interacting protein (GIT1) and the cdc42 guanine exchange factor, \u03b2PIX (Pak interactive exchange factor). Assembly of the Pak\u2013GIT1\u2013\u03b2PIX\u2013paxillin complex was necessary for cdc42 and neuronal Wiskott\u2013Aldrich syndrome protein (N\u2010WASP) activation, actin polymerization and contraction in response to ACh. RhoA activation was also required for the recruitment of Pak to adhesion junctions, Pak activation, paxillin Ser273 phosphorylation and paxillin complex assembly. These studies demonstrate a novel role for Pak in the regulation of N\u2010WASP activation, actin dynamics and cell contractility.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp272132","type":"journal-article","created":{"date-parts":[[2016,4,2]],"date-time":"2016-04-02T17:34:36Z","timestamp":1459618476000},"page":"4879-4900","source":"Crossref","is-referenced-by-count":34,"title":["p21\u2010Activated kinase (Pak) regulates airway smooth muscle contraction by regulating paxillin complexes that mediate actin polymerization"],"prefix":"10.1113","volume":"594","author":[{"given":"Wenwu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cellular and Integrative Physiology Indiana University School Medicine  Indianapolis IN 46202\u20105120 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youliang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology Indiana University School Medicine  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