{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:10:21Z","timestamp":1792005021660,"version":"4.4.0"},"reference-count":36,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,9,18]]},"abstract":"<jats:p>Neuronal Wiskott-Aldrich Syndrome protein (N-WASP) transmits signals from Cdc42 to the nucleation of actin filaments by Arp2\/3 complex. Although full-length N-WASP is a weak activator of Arp2\/3 complex, its activity can be enhanced by upstream regulators such as Cdc42 and PI(4,5)P2. We dissected this activation reaction and found that the previously described physical interaction between the NH2-terminal domain and the COOH-terminal effector domain of N-WASP is a regulatory interaction because it can inhibit the actin nucleation activity of the effector domain by occluding the Arp2\/3 binding site. This interaction between the NH2- and COOH termini must be intramolecular because in solution N-WASP is a monomer. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) influences the activity of N-WASP through a conserved basic sequence element located near the Cdc42 binding site rather than through the WASp homology domain 1. Like Cdc42, PI(4,5)P2 reduces the affinity between the NH2- and COOH termini of the molecule. The use of a mutant N-WASP molecule lacking this basic stretch allowed us to delineate a signaling pathway in Xenopus extracts leading from PI(4,5)P2 to actin nucleation through Cdc42, N-WASP, and Arp2\/3 complex. In this pathway, PI(4,5)P2 serves two functions: first, as an activator of N-WASP; and second, as an indirect activator of Cdc42.<\/jats:p>","DOI":"10.1083\/jcb.150.6.1299","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:45:41Z","timestamp":1027701941000},"page":"1299-1310","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":554,"title":["Mechanism of N-Wasp Activation by Cdc42 and Phosphatidylinositol 4,5-Bisphosphate"],"prefix":"10.1083","volume":"150","author":[{"given":"Rajat","family":"Rohatgi","sequence":"first","affiliation":[{"name":"aDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-yi Henry","family":"Ho","sequence":"additional","affiliation":[{"name":"aDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc W.","family":"Kirschner","sequence":"additional","affiliation":[{"name":"aDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2000,9,18]]},"reference":[{"key":"2023072902325449100_Abdul-Mananetal1999","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/20726","article-title":"Structure of Cdc42 in complex with the GTPase-binding domain of the \u2018Wiskott-Aldrich Syndrome\u2019 protein","volume":"399","author":"Abdul-Manan","year":"1999","journal-title":"Nature"},{"key":"2023072902325449100_Aspenstrometal1996","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0960-9822(02)00423-2","article-title":"Two GTPases, Cdc42 and Rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott-Aldrich Syndrome","volume":"6","author":"Aspenstrom","year":"1996","journal-title":"Curr. 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