title: Regulation of cell migration and survival by focal adhesion targeting of Lasp-1.
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.
authors.affiliation: Department of Immunology, SP231, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Yi Hsing
authors.initials: YH
authors.lastname: Lin
authors.forename: Zee-Yong
authors.initials: ZY
authors.lastname: Park
authors.forename: Dayin
authors.initials: D
authors.lastname: Lin
authors.forename: Anar A
authors.initials: AA
authors.lastname: Brahmbhatt
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rio
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klemke
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D006133:Growth Substances; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C490692:Lasp1 protein, mouse; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; C496051:Ptk2 protein, mouse