Signal transmission by many cell surface receptors results in the activation of phosphoinositide (PI) 3-kinases that phosphorylate the 3’ position of polyphosphoinositides. From a screen for mouse proteins that bind phosphoinositides, the protein GRP1 was identified. GRP1 binds phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P-3] through a pleckstrin homology (PH) domain and displaysa region of high sequence similarity to the yeast Sec7 protein. The PH domain of the closely related protein cytohesin-1, which, through its Sec7 homology domain, regulates integrin beta 2 and catalyzes guanine nucleotide exchange of the small guanine nucleotide-binding protein ARF1, was also found to specifically bind PtdIns(3,4,5)P-3. GRP1 and cytohesin-1 appear to connect receptor-activated PI 3-kinase signaling pathways with proteins that mediate biological responses such as cell adhesion and membrane trafficking.