{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:09:44Z","timestamp":1791216584013,"version":"4.1.0"},"reference-count":38,"publisher":"The Company of Biologists","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:p>Neural Wiskott\u2013Aldrich syndrome protein (N-WASP) is involved in tight regulation of actin polymerization and dynamics. N-WASP activity is regulated by intramolecular interaction, binding to small GTPases and tyrosine phosphorylation. Here, we report on a novel regulatory mechanism; we demonstrate that N-WASP interacts with dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A). In vitro kinase assays indicate that Dyrk1A directly phosphorylates the GTPase-binding domain (GBD) of N-WASP at three sites (Thr196, Thr202 and Thr259). Phosphorylation of the GBD by Dyrk1A promotes the intramolecular interaction of the GBD and verprolin, cofilin and acidic (VCA) domains of N-WASP, and subsequently inhibits Arp2\/3-complex-mediated actin polymerization. Overexpression of either Dyrk1A or a phospho-mimetic N-WASP mutant inhibits filopodia formation in COS-7 cells. By contrast, the knockdown of Dyrk1A expression or overexpression of a phospho-deficient N-WASP mutant promotes filopodia formation. Furthermore, the overexpression of a phospho-mimetic N-WASP mutant significantly inhibits dendritic spine formation in primary hippocampal neurons. These findings suggest that Dyrk1A negatively regulates actin filament assembly by phosphorylating N-WASP, which ultimately promotes the intramolecular interaction of its GBD and VCA domains. These results provide insight on the mechanisms contributing to diverse actin-based cellular processes such as cell migration, endocytosis and neuronal differentiation.<\/jats:p>","DOI":"10.1242\/jcs.086124","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T03:52:35Z","timestamp":1326772355000},"page":"67-80","source":"Crossref","is-referenced-by-count":46,"title":["Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP"],"prefix":"10.1242","volume":"125","author":[{"given":"Joongkyu","family":"Park","sequence":"first","affiliation":[{"name":"Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120\u2013749, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee Young","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120\u2013749, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joohyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University, College of Medicine, Seoul 110\u2013799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo-Joo","family":"Song","sequence":"additional","affiliation":[{"name":"Graduate Program in Neuroscience, Institute for Brain Science and Technology, FIRST Research Group, Inje University, Busan 633-146, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunghoe","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University, College of Medicine, Seoul 110\u2013799, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang Chul","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120\u2013749, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042521451418400_R1","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.bbrc.2006.10.169","article-title":"MNB\/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins","volume":"351","author":"Adayev","year":"2006","journal-title":"Biochem. 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Chem."},{"key":"2021042521451418400_R7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.4161\/cib.3.2.10759","article-title":"Regulation of WASp by phosphorylation: activation or other functions?","volume":"3","author":"Dovas","year":"2010","journal-title":"Commun. Integr. Biol."},{"key":"2021042521451418400_R8","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1007\/BF00294247","article-title":"Down's syndrome and Alzheimer's disease: dendritic spine counts in the hippocampus","volume":"79","author":"Ferrer","year":"1990","journal-title":"Acta Neuropathol."},{"key":"2021042521451418400_R9","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1111\/j.1742-4658.2009.07346.x","article-title":"Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation","volume":"276","author":"Gockler","year":"2009","journal-title":"FEBS J."},{"key":"2021042521451418400_R10","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nrm2026","article-title":"The ARP2\/3 complex: an actin nucleator comes of age","volume":"7","author":"Goley","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042521451418400_R11","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1074\/jbc.275.4.2431","article-title":"Specificity determinants of substrate recognition by the protein kinase DYRK1A","volume":"275","author":"Himpel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021042521451418400_R12","doi-asserted-by":"crossref","first-page":"7086","DOI":"10.1073\/pnas.111146798","article-title":"Cytoskeletal microdifferentiation: a mechanism for organizing morphological plasticity in dendrites","volume":"98","author":"Kaech","year":"2001","journal-title":"Proc. Natl. Acad. Sci. 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