βPix is a New Player in Renal Physiology

cytoskeletal reorganization, morphogenesis, and cell migration (Figure 1). β 1 Pix also exhibits non-canonical activities in which it serves as a scaffolding protein in some signaling pathways (Pavlov et al., 2010). Staruschenko and Sorokin (2012) also provide an overview of the expression of βPix in the kidney and the various roles of βPix in kidney function. Recently, βPix expression has been detected in mesangial cells, podocytes, cortical collecting ducts, and localized vessels and vascular smooth muscle cells of the rat kidney and in a number of nephron segment-specific derived cell lines (antibodies against βPix were unable to discriminate between the β 1 Pix and β 2 Pix isoforms, Pavlov et al., 2010). These findings set the stage for unraveling the roles of βPix in renal physiology, which is presented under four categories (Staruschenko and Sorokin, 2012): (i) regulation of ion transport, (ii) regulation of glomerular function, (iii) regulation of urothelial signaling, and (iv) complexity of βPix signaling in the kidney. One of the most exciting advances in our understanding of β 1 Pix function in the kidney involves the role of β 1 Pix in regulating the epithelial sodium channel (ENaC) in the cortical collecting duct. Staruschenko and colleagues (Pavlov et al., 2010) have recently demonstrated that endothelin-1 signals through β 1 Pix to decrease the number of ENaC channels in the apical cell membrane of cortical collecting duct cells. β 1 Pix negatively regulates ENaC by binding to 14-3-3 proteins and disrupting the interaction between 14-3-3 proteins and the E3 ubiquitin ligase Nedd4-2. A major regulator of ENaC, Nedd4-2 ubiquitinates cell surface ENaC, marking the channel for internalization and degradation. Since 14-3-3 proteins inhibit Nedd4-2 activity, β 1 Pix blocks 14-3-3 proteins from interacting and inhibiting a handful of reviews that address the biology and function of βPix and the related GEF αPix (Bagrodia and Cerione, 1999; Rosenberger and Kutsche, 2006; Frank and Hansen, 2008; Schlenker and Rittinger, 2009; Momboisse et al., 2010). For those readers unfamiliar with β-Pix (ARHGEF 7), this protein has had a number of previous names including COOL1, KIAA0142, P50BP, P85, P85SPR, PAK3, and PixB (HUGO Gene Nomenclature Committee; http://www.genenames.org/ data/hgnc_data.php?hgnc_id=15607). Oh et al. (1997) originally demonstrated that p85SPR [Src Homology 3 (SH3) domain containing proline-rich protein], now known as βPix, interacted with areas of focal adhesion, suggesting a role for βPix in cytoskeletal function. Shortly thereafter, Manser et al. (1998) reported the binding of βPix (and αPix) to PAK1. Further, Bagrodia et al. (1998) identified βPix (named p85Cool-1) and a smaller alterative splice variant (p50Cool-1) as two proteins that facilitated interactions between PAK and DBL homology (DH) and pleckstrin homology (PH) domains. Finally, Koh et al. (2001) reported an isoform of βPix designated β 2 Pix; that isoform contained a serine-rich region not found in the original βPix protein (which is now designated as β 1 Pix-a, Kim et al., 2000) nor the β 1 Pix-b and β 1 Pix-c isoforms (Oh et al., 1997; Kim et al., 2000). The structure and functional domains of β 1 Pix are provided in Figure 1. There are a number of functions of β 1 -Pix. Staruschenko and Sorokin (2012) describe that β 1 Pix participates in both canonical and non-canonical signaling pathways involved in various cellular functions (see Figure 1). The canonical signaling of β 1 Pix results from its GEF activity, which activates Rac1 and Cdc42, and regulates various cellular functions including A commentary on