Physiological functions of the Akt substrate Girdin and its family proteins and their roles in pathogenesis

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We investigated the physiological roles of Akt substrate Girdin using a variety of cell lines and gene-targeting mice. Girdin knockdown by siRNA in various cell lines including fibroblasts, cancer cells, endothelial cells and vascular smooth muscle cells, significantly impaired their migration. Impaired cell migration by Girdin knockdown was due to the impairment of lamellipodia formation at the leading edge of migrating cells, suggesting that Girdin plays a role in actin reorganization at the leading edge. In addition, analysis of Girdin knockout mice demonstrated that Girdin plays a crucial role in postnatal angiogenesis and neurogenesis. Vascular development in the retina and brain cortex in Girdin knockout mice decreased to 60-70% compared with that of wild-type mice. Girdin deficiency also leads to overextended migration and mispositioning of the dentate granule cells, resulting in profound cytoarchitectural disorganization of the dentate gyrus which is known to develop during the early postnatal period. A novel Girdin family protein, Gipie, is expressed in endothelial cells, where it interacts with GRP78, a master regulator of ER stress. Our study indicated that Gipie/GRP78 interaction protects endothelial cells against ER stree-induced apoptosis.