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

Vijayakumar, V., Monypenny, J., Chen, X. J., Machesky, L. M. , Lilla, S., Thrasher, A. J., Anton, I. M., Calle, Y. and Jones, G. E. (2015) Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages. Journal of Cell Science, 128(2), pp. 251-265. (doi:10.1242/jcs.154880)

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Publisher's URL: http://dx.doi.org/10.1242/jcs.154880

Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Machesky, Professor Laura and Lilla, Dr Sergio
Authors: Vijayakumar, V., Monypenny, J., Chen, X. J., Machesky, L. M., Lilla, S., Thrasher, A. J., Anton, I. M., Calle, Y., and Jones, G. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Cell Science
Publisher:The Company of Biologists Ltd.
ISSN:0021-9533
ISSN (Online):1477-9137
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Journal of Cell Science 128(2):251-265
Publisher Policy:Reproduced under a Creative Commons License
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