Involvement of Girdin in the Determination of Cell Polarity during Cell Migration

Abstract

Cell migration is a critical cellular process that determines embryonic development and the progression of human diseases. Therefore, cell- or context-specific mechanisms by which multiple promigratory proteins differentially regulate cell migration must be analyzed in detail. Girdin (girders of actin filaments) (also termed GIV, Gα-interacting vesicle associated protein) is an actin-binding protein that regulates migration of various cells such as endothelial cells, smooth muscle cells, neuroblasts, and cancer cells. Here we show that Girdin regulates the establishment of cell polarity, the deregulation of which may result in the disruption of directional cell migration. We found that Girdin interacts with Par-3, a scaffolding protein that is a component of the Par protein complex that has an established role in determining cell polarity. RNA interference-mediated depletion of Girdin leads to impaired polarization of fibroblasts and mammary epithelial cells in a way similar to that observed in Par-3-depleted cells. Accordingly, the expression of Par-3 mutants unable to interact with Girdin abrogates cell polarization in fibroblasts. Further biochemical analysis suggests that Girdin is present in the Par protein complex that includes Par-3, Par-6, and atypical protein kinase C. Considering previous reports showing the role of Girdin in the directional migration of neuroblasts, network formation of endothelial cells, and cancer invasion, these data may provide a specific mechanism by which Girdin regulates cell movement in biological contexts that require directional cell movement.

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

“…In this study, we confirmed that PAR-3 physically interacts with Girdin, which is consistent with previous studies (Brajenovic et al, 2004;Ohara et al, 2012). Furthermore, we found that PAR-3 upregulates Girdin expression through AP-2-induced Girdin transcription.…”

“…A recent study reported that Girdin physically interacts with PAR-3 (Brajenovic et al, 2004;Ohara et al, 2012). We confirmed that the Girdin C-terminus including the CT domain preferentially binds to PAR-3 and that the PAR-3 C-terminus is required for its interaction with the Girdin C-terminus (supplementary material Fig.…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…GIV/Girdin knockout mice exhibit defects in angiogenesis, neurogenesis, and cell motility (Enomoto et al, 2005;Kitamura et al, 2008;Wang et al, 2011). The action of GIV on cell motility may relate in part to its ability to interact with the partitioning defective (PAR) protein complex (Ohara et al, 2012). GIV is also localized to the centrosome and the midbody as observed for AGS5 (Blumer et al, 2006;Mao et al, 2012).…”

Akt–Girdin Signaling in Cancer-Associated Fibroblasts Contributes to Tumor Progression

“…Girdin is phosphorylated by Akt, which functions downstream of PI3K activation to regulate cell migration and polarization (28)(29)(30)(31)(32). In this study, we used a knock-in mouse line (designated SA mice) engineered to express a Girdin mutant that lacks the Akt phosphorylation site at Serine 1416 (S1416A).…”