IDENTIFICATION OF A SPECIFIC INS(1,3,4,5)P-4-BINDING PROTEIN AS A MEMBER OF THE GAP1 FAMILY

INOSITOL 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P-4) is produced rapid ly from inositol 1,4,5-trisphosphate (Ins(1,4,5)P-3) in stimulated cel ls(1,2). Despite extensive experimentation, no clearly defined cellula r function has yet been described for this inositol phosphate. Binding sites specific for Ins(1,3,4,5)P-4 have been identified in several ti ssues(3,4), and we have purified one such protein to homogeneity(5). I ts high affinity for Ins(1,3,4,5)P-4, and its exquisite specificity fo r this isomeric configuration(5,6), suggest it may be an Ins(1,3,4,5)P -4 receptor. Here we report the cloning and characterization of this p rotein as a GTPase-activating protein, specifically a member of the GA P family. In vitro it shows GAP activity against both Rap and Ras, but only the Ras GAP activity is inhibited by phospholipids and is specif ically stimulated by Ins(1,3,4,5)P-4.