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J Cell Sci. 2012 Jan 1;125(Pt 1):67-80. doi: 10.1242/jcs.086124. Epub 2012 Jan 16.

Dyrk1A negatively regulates the actin cytoskeleton through threonine phosphorylation of N-WASP.

Author information

1
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.

Abstract

Neural Wiskott-Aldrich 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.

PMID:
22250195
DOI:
10.1242/jcs.086124
[Indexed for MEDLINE]
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