Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages
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 c...
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The Company of Biologists
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294773/ |
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pubmed-42947732015-01-27 Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages Vijayakumar, Vineetha Monypenny, James Chen, Xing Judy Machesky, Laura M. Lilla, Sergio Thrasher, Adrian J. Antón, Inés M. Calle, Yolanda Jones, Gareth E. Research Article 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. The Company of Biologists 2015-01-15 /pmc/articles/PMC4294773/ /pubmed/25413351 http://dx.doi.org/10.1242/jcs.154880 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Vijayakumar, Vineetha Monypenny, James Chen, Xing Judy Machesky, Laura M. Lilla, Sergio Thrasher, Adrian J. Antón, Inés M. Calle, Yolanda Jones, Gareth E. |
| spellingShingle |
Vijayakumar, Vineetha Monypenny, James Chen, Xing Judy Machesky, Laura M. Lilla, Sergio Thrasher, Adrian J. Antón, Inés M. Calle, Yolanda Jones, Gareth E. Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| author_facet |
Vijayakumar, Vineetha Monypenny, James Chen, Xing Judy Machesky, Laura M. Lilla, Sergio Thrasher, Adrian J. Antón, Inés M. Calle, Yolanda Jones, Gareth E. |
| author_sort |
Vijayakumar, Vineetha |
| title |
Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| title_short |
Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| title_full |
Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| title_fullStr |
Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| title_full_unstemmed |
Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages |
| title_sort |
tyrosine phosphorylation of wip releases bound wasp and impairs podosome assembly in macrophages |
| description |
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. |
| publisher |
The Company of Biologists |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294773/ |
| _version_ |
1613176798355390464 |