Identification of a specific lns(l,3,4,5)P4-binding protein as a member of the GAP1 family

INOSITOL 1,3,4,5-tetrakisphosphate (Ins(l,3,4,5)P4) is produced rapidly from inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) in stimulated cells1,2. Despite extensive experimentation, no clearly defined cellular function has yet been described for this inositol phosphate. Binding sites specific for Ins(l,3,4,5)P4 have been identified in several tissues3,4, and we have purified one such protein to homogeneity5. Its high affinity for Ins(l,3,4,5)P4, and its exquisite specificity for this isomeric configuration5,6, suggest it may be an Ins(l,3,4,5)P4 receptor. Here we report the cloning and characterization of this protein as a GTPase-activating protein, specifically a member of the GAP1 family. In vitro it shows GAP activity against both Rap and Ras, but only the Ras GAP activity is inhibited by phospholipids and is specifically stimulated by Ins(l,3,4,5)P4.

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