MetadataShow full item record
AbstractBACKGROUND: The chemokine receptor CXCR2 plays a pivotal role in migration of neutrophils, macrophages and endothelial cells, modulating several biological responses such as angiogenesis, wound healing and acute inflammation. CXCR2 is also involved in pathogenesis of chronic inflammation, sepsis and atherosclerosis. The ability of CXCR2 to associate with a variety of proteins dynamically is responsible for its effects on directed cell migration or chemotaxis. The dynamic network of such CXCR2 binding proteins is termed as "CXCR2 chemosynapse". Proteomic analysis of proteins that co-immunoprecipitated with CXCR2 in neutrophil-like dHL-60 cells revealed a novel protein, LIM and SH3 protein 1 (LASP-1), binds CXCR2 under both basal and ligand activated conditions. LASP-1 is an actin binding cytoskeletal protein, involved in the cell migration. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that CXCR2 and LASP-1 co-immunoprecipitate and co-localize at the leading edge of migrating cells. The LIM domain of LASP-1 directly binds to the carboxy-terminal domain (CTD) of CXCR2. Moreover, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4. Using a site-directed and deletion mutagenesis approach, Iso323-Leu324 of the conserved LKIL motif on CXCR2-CTD was identified as the binding site for LASP-1. Interruption of the interaction between CXCR2-CTD and LIM domain of LASP-1 by dominant negative and knock down approaches inhibited CXCR2-mediated chemotaxis. Analysis for the mechanism for inhibition of CXCR2-mediated chemotaxis indicated that LASP-1/CXCR2 interaction is essential for cell motility and focal adhesion turnover involving activation of Src, paxillin, PAK1, p130CAS and ERK1/2. CONCLUSIONS/SIGNIFICANCE: We demonstrate here for the first time that LASP-1 is a key component of the "CXCR2 chemosynapse" and LASP-1 interaction with CXCR2 is critical for CXCR2-mediated chemotaxis. Furthermore, LASP-1 also directly binds the CTD of CXCR1, CXCR3 and CXCR4, suggesting that LASP-1 is a general mediator of CXC chemokine mediated chemotaxis. Thus, LASP-1 may serve as a new link coordinating the flow of information between chemokine receptors and nascent focal adhesions, especially at the leading edge. Thus the association between the chemokine receptors and LASP-1 suggests to the presence of a CXC chemokine receptor-LASP-1 pro-migratory module in cells governing the cell migration.
CitationPLoS One. 2010 Apr 19; 5(4):e10050
- Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1.
- Authors: Li B, Zhuang L, Trueb B
- Issue date: 2004 May 7
- IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse".
- Authors: Neel NF, Sai J, Ham AJ, Sobolik-Delmaire T, Mernaugh RL, Richmond A
- Issue date: 2011
- Investigating lasp-2 in cell adhesion: new binding partners and roles in motility.
- Authors: Bliss KT, Chu M, Jones-Weinert CM, Gregorio CC
- Issue date: 2013 Apr
- Contribution of the LIM domain and nebulin-repeats to the interaction of Lasp-2 with actin filaments and focal adhesions.
- Authors: Nakagawa H, Suzuki H, Machida S, Suzuki J, Ohashi K, Jin M, Miyamoto S, Terasaki AG
- Issue date: 2009 Oct 23
- LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
- Authors: Duvall-Noelle N, Karwandyar A, Richmond A, Raman D
- Issue date: 2016 Mar 3