α-actinin-4 is essential for maintaining the spreading, motility and contractility of fibroblastsα-actinin-4维持传播至关重要,能动性和成纤维细胞的收缩性.pdfVIP

a-Actinin-4 Is Essential for Maintaining the Spreading, Motility and Contractility of Fibroblasts 1 2 3 1,4 Hanshuang Shao , James H.-C. Wang , Martin R. Pollak , Alan Wells * 1 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 3 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America, 4 Pittsburgh VA Health System, Pittsburgh, Pennsylvania, United States of America Abstract Background: a-Actinins cross-link actin filaments, with this cross-linking activity regulating the formation of focal adhesions, intracellular tension, and cell migration. Most non-muscle cells such as fibroblasts express two isoforms, a-actinin-1 (ACTN1) and a-actinin-4 (ACTN4). The high homology between these two isoforms would suggest redundancy of their function, but recent studies have suggested different regulatory roles. Interestingly, ACTN4 is phosphorylated upon growth factor stimulation, and this loosens its interaction with actin. Methodology/Principal Findings: Using molecular, biochemical and cellular techniques, we probed the cellular functions of ACTN4 in fibroblasts. Knockdown of ACTN4 expression in murine lung fibroblasts significantly impaired cell migration, spreading, adhesion, and proliferation. Surprisingly, knockdown of ACTN4 enhanced cellular compaction and contraction force, and increased cellular and nuclear cross-sectional area. These results, except the increased contractility, are consistent with a putative role of ACTN4 in cytokinesis. F