Regulation of cell migration and survival by focal adhesion targeting of Lasp-1.
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.
Lin
Yi Hsing
YH
Department of Immunology, SP231, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Park
Zee-Yong
ZY
Lin
Dayin
D
Brahmbhatt
Anar A
AA
Rio
Marie-Christine
MC
Yates
John R
JR
Klemke
Richard L
RL
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*
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