Signaling by Phosphoinositide-3,4,5-trisphosphate Through Proteins Containing Pleckstrin and Sec7 Homology Domains

• Published in: Science (American Association for the Advancement of Science) 1997-03, Vol.275 (5308), p.1927-1930
• Main Authors: Klarlund, Jes K., Guilherme, Adilson, Holik, John J., Virbasius, Joseph V., Chawla, Anil, Czech, Michael P.
• Format: Article
• Language: English
• Subjects: Adipocytes - chemistry; ADP-Ribosylation Factor 1; ADP-Ribosylation Factors; Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Blood Proteins - chemistry; Brain; Brain Chemistry; CD18 Antigens - metabolism; Cell adhesion; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; Cell Membrane - metabolism; Cell physiology; Cells, Cultured; Cellular signal transduction; Cellulose nitrate; Cloning, Molecular; Complementary DNA; DNA, Complementary; Fundamental and applied biological sciences. Psychology; Fungal Proteins - chemistry; GTP-Binding Proteins - metabolism; Guanine Nucleotide Exchange Factors; Humans; Integrins; Libraries; Lipids; Mice; Molecular and cellular biology; Molecular biology; Molecular Sequence Data; Phosphatidylinositol; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositols; Phosphoinositides; Phosphoproteins; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein isoforms; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Responses to growth factors, tumor promotors, other factors; Rodents; Screening Tests; Sequence Homology, Amino Acid; Signal Transduction
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.275.5308.1927

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 displays a 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 β2 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.