Biological membranes undergo continuous remodeling during cell movement and in processes that transfer material between organelles while maintaining organellar identity and affect the assembly and reassembly of organelles necessary for progression through mitosis. The main objective of the work in this laboratory is to elucidate the mechanisms that regulate the membrane remodeling. The role of the Arf family of GTP-binding proteins has been our focus. We have found a family of GTPase-activating proteins (GAPs) for Arf, the ASAP/ACAP family, which contain PH, Arf GAP and ANK repeat domains. All tested members of the family function as GAPs in vitro. We have found that these proteins are specific for particular Arfs both in vitro and in vivo. In addition, the GAP activity of these proteins is dependent on two phospholipids, phosphatidic acid and a phosphoinositide. The different ASAP/ACAP family members also show specificity for the particular phospoinositide isomer, some being activated by phosphatatidylinositol 4,5 bisphosphate and others activated by phosphatidylinositol 3,4,5 trisphosphate. The PH domain regulates activity by a mechanism not previously described for this motif. Two members of the family have een found to bind Src and FAK family proteins, and one of these has been shown to regulate the cycle of events that result in cell migration. Current work is aimed at identifying the cellular functions of other members of the family, including a possible role of one member, which is found on a chromosomal locus linked to neuroblastoma, in malignant transformation. Z01 BC 07365-03 LBC to LCO
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