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      Interaction of Alpha-Actinin-4 with Class I PxxP Motif-Containing OK/SW-CL.16 Protein

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          Background: The aim of this study was to identify novel binding partners for α-actinin-4 (actinin-4), an essential component of the glomerular filtration barrier. Methods: We performed bacterial two-hybrid screenings of a human kidney cDNA library using as a bait human actinin-4 containing the spectrin-like repeat R1. The identified interactions were further verified by in vitro affinity assays. To investigate the expression of the identified molecules in the kidney and other tissues, a human tissue cDNA panel screening and in situ hybridization were performed. Results: One isolated cDNA from the library encoded OK/SW-CL.16 protein with a segment similar to known actinin-interacting regions. OK/SW-CL.16 protein also contained the class I PxxP motif, which can participate in binding to Src homology 3 (SH3) domain-containing signaling proteins. In vitro affinity assays showed interactions of recombinant actinin-4 R1 and full-length renal actinin-4 with recombinant OK/SW-CL.16 protein. A tissue cDNA panel screening revealed a ubiquitous expression of OK/SW-CL.16 mRNA.In situ hybridization showed glomerular expression of OK/SW-CL.16 mRNA, mainly in podocytes and mesangial cells. Conclusion: Our results suggest that OK/SW-CL.16 protein is a novel binding partner for actinin-4. OK/SW-CL16 protein might act as a linker between actinin-4 and some SH3 domain-containing signaling proteins in podocytes.

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          Most cited references 17

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          Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

          Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.
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            Actinin-4, a Novel Actin-bundling Protein Associated with Cell Motility and Cancer Invasion

            Regulation of the actin cytoskeleton may play a crucial role in cell motility and cancer invasion. We have produced a monoclonal antibody (NCC- Lu-632, IgM, k) reactive with an antigenic protein that is upregulated upon enhanced cell movement. The cDNA for the antigen molecule was found to encode a novel isoform of nonmuscle α-actinin. This isoform (designated actinin-4) was concentrated in the cytoplasm where cells were sharply extended and in cells migrating and located at the edge of cell clusters, but was absent from focal adhesion plaques or adherens junctions, where the classic isoform (actinin-1) was concentrated. Actinin-4 shifted steadily from the cytoplasm to the nucleus upon inhibition of phosphatidylinositol 3 kinase or actin depolymerization. The cytoplasmic localization of actinin-4 was closely associated with an infiltrative histological phenotype and correlated significantly with a poorer prognosis in 61 cases of breast cancer. These findings suggest that cytoplasmic actinin-4 regulates the actin cytoskeleton and increases cellular motility and that its inactivation by transfer to the nucleus abolishes the metastatic potential of human cancers.
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              Alpha-actinin revisited: a fresh look at an old player.


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2007
                20 September 2007
                : 107
                : 2
                : e65-e72
                aThird Department of Internal Medicine, Akita University School of Medicine, Akita, and bDivision of Nephrology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan
                108644 Nephron Exp Nephrol 2007;107:e65–e72
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 10, References: 23, Pages: 1
                Original Paper


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