Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages.

Vineetha Vijayakumar, James Monypenny, Xing Judy Chen, Laura M Machesky, Sergio Lilla, Adrian J Thrasher, Inés M Antón, Yolanda Calle, Gareth E Jones

Journal of cell science 2015 Jan 15

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Podosomes are integrin-containing adhesion structures commonly found in migrating leukocytes of the monocytic lineage. The actin cytoskeletal organisation of podosomes is based on a WASP- and Arp2/3-mediated mechanism. WASP also associates with a second protein, WIP (also known as WIPF1), and they co-localise in podosome cores. Here, we report for the first time that WIP can be phosphorylated on tyrosine residues and that tyrosine phosphorylation of WIP is a trigger for release of WASP from the WIP-WASP complex. Using a knockdown approach together with expression of WIP phosphomimics, we show that in the absence of WIP-WASP binding, cellular WASP is rapidly degraded, leading to disruption of podosomes and a failure of cells to degrade an underlying matrix. In the absence of tyrosine phosphorylation, the WIP-WASP complex remains intact and podosome lifetimes are extended. A screen of candidate kinases and inhibitor-based assays identified Bruton's tyrosine kinase (Btk) as a regulator of WIP tyrosine phosphorylation. We conclude that tyrosine phosphorylation of WIP is a crucial regulator of WASP stability and function as an actin-nucleation-promoting factor. © 2015. Published by The Company of Biologists Ltd.

Citation

Vineetha Vijayakumar, James Monypenny, Xing Judy Chen, Laura M Machesky, Sergio Lilla, Adrian J Thrasher, Inés M Antón, Yolanda Calle, Gareth E Jones. Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages. Journal of cell science. 2015 Jan 15;128(2):251-65