title: Filamin A phosphorylation by Akt promotes cell migration in response to arsenic.
abstract: We had previously reported that trivalent arsenic (As(3+)), a well-known environmental carcinogen, induces phosphorylation of several putative Akt substrates. In the present report, we characterized one of these substrates by immunoprecipitation and proteomics analysis. The results indicate that a cytoskeleton remodeling protein, filamin A, with a molecular weight around 280 kDa, is phosphorylated by Akt in HEK-293 cells treated with As(3+), which was also confirmed in human bronchial epithelial cell line, BEAS-2B cells. Additional biochemical and biological studies revealed that serine 2152 (S2152) of filamin A is phosphorylated by activated Akt in the cells treated with As(3+). To further confirm the importance of Akt-dependent filamin A S2152 phosphorylation in As(3+)-induced cell migration, we over-expressed either wild type filamin A or the mutated filamin A in which the S2152 was substituted with alanine (S2152A). The capability of cell migration was reduced significantly in the cells expressing the mutated filamin A (S2152A). Clinically, we found that increased expression of filamin A predicts poorer overall survival of the lung cancer patients with adenocarcinoma. Thus, these data suggest that Akt dependent filamin A phosphorylation is one of the key events in mediating As(3+)-induced carcinogenesis. Antagonizing Akt signaling can ameliorate As(3+)-induced filamin A phosphorylation and cell migration, which may serve as a molecular targeting strategy for malignancies associated with environmental As(3+) exposure.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Yongju
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.|The Proteomics Core and Institute of Environmental Health Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stemmer
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
mesh_terms: D001151:Arsenic / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement; D064448:Filamins / Q000737:chemistry*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D064448:Filamins; D051057:Proto-Oncogene Proteins c-akt; D001151:Arsenic
keywords: Akt; arsenic; filamin A; migration; patient survival