Abstract
Large-scale proteomic and functional analysis of isolated pseudopodia revealed the Lim, actin, and SH3 domain protein (Lasp-1) as a novel protein necessary for cell migration, but not adhesion to, the extracellular matrix (ECM). Lasp-1 is a ubiquitously expressed actin-binding protein with a unique domain configuration containing SH3 and LIM domains, and is overexpressed in 8-12% of human breast cancers. We find that stimulation of nonmotile and quiescent cells with growth factors or ECM proteins facilitates Lasp-1 relocalization from the cell periphery to the leading edge of the pseudopodium, where it associates with nascent focal complexes and areas of actin polymerization. Interestingly, although Lasp-1 dynamics in migratory cells occur independently of c-Abl kinase activity and tyrosine phosphorylation, c-Abl activation by apoptotic agents specifically promotes phosphorylation of Lasp-1 at tyrosine 171, which is associated with the loss of Lasp-1 localization to focal adhesions and induction of cell death. Thus, Lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ECM proteins.
Copyright the Rockefeller University Press
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / biosynthesis
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Carcinoma / genetics
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Carcinoma / metabolism
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Cell Movement / genetics*
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Cell Survival / genetics
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Cytoskeletal Proteins
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Extracellular Matrix Proteins / metabolism
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Extracellular Matrix Proteins / pharmacology
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Focal Adhesions / genetics
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Focal Adhesions / metabolism*
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Growth Substances / metabolism
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Growth Substances / pharmacology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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LIM Domain Proteins
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Mice
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NIH 3T3 Cells
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Neoplasm Metastasis / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphorylation
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Protein Transport / drug effects
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Protein Transport / genetics
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-abl / metabolism
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Pseudopodia / genetics
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Pseudopodia / metabolism*
Substances
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Actins
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Cytoskeletal Proteins
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Extracellular Matrix Proteins
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Growth Substances
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Homeodomain Proteins
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LIM Domain Proteins
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Lasp1 protein, mouse
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Neoplasm Proteins
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-abl
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Ptk2 protein, mouse