title: Matricellular protein Cyr61 bridges lysophosphatidic acid and integrin pathways leading to cell migration.
abstract: Lysophosphatidic acid (LPA), a potent bioactive lipid found in atherosclerotic lesions, markedly induces smooth muscle cell (SMC) migration, which is an important process in atherogenesis. Therefore, understanding the mechanism of LPA-induced SMC migration is important. Several microarray databases suggest that the matricellular protein Cyr61 is highly induced by LPA. We hypothesized that Cyr61 mediates LPA-induced cell migration. Our data show that LPA induced temporal and spatial expression of Cyr61, which promptly accumulated in the cellular Golgi apparatus and then translocated to the extracellular matrix. Cyr61 antibody blockade and siRNA inhibition both diminished LPA-induced SMC migration, indicating a novel regulatory role of Cyr61. SMCs derived from LPA receptor 1 (LPA1) knock-out mice lack the ability of Cyr61 induction and cell migration, supporting the concept that LPA1 is required for Cyr61 expression and migration. By contrast, PPARγ was not found to be involved in LPA-mediated effects. Furthermore, focal adhesion kinase (FAK), a nonreceptor tyrosine kinase important for regulating cell migration, was activated by LPA at a late time frame coinciding with Cyr61 accumulation. Interestingly, knockdown of Cyr61 blocked LPA-induced FAK activation, indicating that an LPA-Cyr61-FAK axis leads to SMC migration. Our results further demonstrate that plasma membrane integrins α6β1 and ανβ3 transduced the LPA-Cyr61 signal toward FAK activation and migration. Taken together, these data reveal that de novo Cyr61 in the extracellular matrix bridges LPA and integrin pathways, which in turn, activate FAK, leading to cell migration. The current study provides new insights into mechanisms underlying cell migration-related disorders, including atherosclerosis, restenosis, and cancers.
authors.affiliation: From the Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996.
authors.forename: Daniel Dongwei
authors.initials: DD
authors.lastname: Wu
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Hao
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Xuemin
authors.initials: X
authors.lastname: Xu
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Cui
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000235:genetics / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D039121:Integrin alpha6beta1; D039302:Integrin alphaVbeta3; D008246:Lysophospholipids; D047495:PPAR gamma; D049368:Receptors, Lysophosphatidic Acid; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C032881:lysophosphatidic acid
keywords: Migration; Protein Kinases; Signal Transduction; Signaling; Vascular Biology