Abstract 18954: Novel Role of De Novo Matricellular Protein Cyr61 in Bridging Lysophosphatidic Acid and Integrin Pathways Leading to Smooth Muscle Cell Migration

Abstract

Lysophosphatidic acid (LPA), a potent bioactive lipid, markedly induces smooth muscle cell (SMC) migration, which is one of the important processes involved in atherosclerotic lesion development. In order to search for key molecules that control LPA-induced SMC migration, we performed gene microarray analysis and attempted to identify LPA-induced extracellular molecules responsible for LPA-triggered cell migration. We observed that LPA selectively induced the expression of the matricellular protein Cyr61, a multifunctional matrix-related protein, which has been implicated in cell angiogenesis, proliferation, adhesion and migration. We hypothesize that Cyr61 mediates LPA-induced cell migration. Our data show that LPA induces temporal and spatial expression of Cyr61 protein in SMCs. LPA-induced de novo Cyr61 proteins promptly accumulate in the Golgi apparatus and then translocate to the extracellular matrix. Cyr61 specific siRNAs diminishes LPA-induced cell migration, indicating the novel regulatory role of the induced matricellular protein Cyr61 in LPA-induced cell migration. Using primary SMCs derived from LPA receptor 1 (LPA1) knockout and LPA2 knockout mice, our data reveal that LPA1 is required for LPA-induced Cyr61 expression in SMCs and cell migration. Furthermore, LPA induces profound activation of focal adhesion kinase (FAK) in SMCs in later time points, coinciding with the accumulation of Cyr61in the extracellular matrix. FAK is an intracellular kinase important in regulating cell migration. Our data demonstrated that knockdown of de novo Cyr61 expression blocked LPA-induced cellular FAK activation and cell migration. Integrin alpha6 and beta1 have been reported to interact with Cyr61 in SMCs. We found that knockdown of the expression of integrin alpha6 or beta1 prevented LPA-induced FAK activation and cell migration. Taken together, these data reveal that a novel LPA/Cyr61 pathway controls cell migration and that de novo Cyr61 in extracellular matrix bridges LPA and integrin signaling, which in turn, activates FAK leading to cell migration. Understanding this novel pathway will provide new insights into mechanisms underlying the development of cell migration related disorders including atherosclerosis and restenosis.