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The LIM and SH3 domain protein family: structural proteins or signal transducers or both?

ABSTRACT: LIM and SH3 Protein 1 (LASP-1) was initially identified from a cDNA library of metastatic axillary lymph nodes (MLN) more than a decade ago. It was found to be overexpressed in human breast and ovarian cancer and became the first member of a newly defined LIM-protein subfamily of the nebulin group characterized by the combined presence of LIM and SH3 domains. LASP2, a novel LASP1-related gene was first identified and characterized in silico. Subsequently it proved to be a splice variant of the Nebulin gene and therefore was also termed LIM/nebulette. LASP-1 and -2 are highly conserved in their LIM, nebulin-like and SH3 domains but differ significantly at their linker regions. Both proteins are ubiquitously expressed and involved in cytoskeletal architecture, especially in the organization of focal adhesions. Here we present the first systematic review to summarize all relevant data concerning their domain organization, expression profiles, regulating factors and function. We compile evidence that both, LASP-1 and LASP-2, are important during early embryo- and fetogenesis and are highly expressed in the central nervous system of the adult. However, only LASP-1 seems to participate significantly in neuronal differentiation and plays an important functional role in migration and proliferation of certain cancer cells while the role of LASP-2 is more structural. The increased expression of LASP-1 in breast tumours correlates with high rates of nodal-metastasis and refers to a possible relevance as a prognostic marker.

SUBMITTER: Grunewald TG

PROVIDER: S-EPMC2359764 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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The LIM and SH3 domain protein family: structural proteins or signal transducers or both?

Grunewald Thomas G P TG Butt Elke E

Molecular cancer 20080417

LIM and SH3 Protein 1 (LASP-1) was initially identified from a cDNA library of metastatic axillary lymph nodes (MLN) more than a decade ago. It was found to be overexpressed in human breast and ovarian cancer and became the first member of a newly defined LIM-protein subfamily of the nebulin group characterized by the combined presence of LIM and SH3 domains. LASP2, a novel LASP1-related gene was first identified and characterized in silico. Subsequently it proved to be a splice variant of the N ...[more]

PMID: 18419822

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Project description:BackgroundThe 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 findingsWe 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/significanceWe 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.

Dataset Information

The LIM and SH3 domain protein family: structural proteins or signal transducers or both?

Publications

The LIM and SH3 domain protein family: structural proteins or signal transducers or both?

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