Accession Number : ADA469536


Title :   Investigation of Novel Molecular Targets for Pleckstrin Homology (PH) Domains Found in Oncogenes Implicated in Breast Cancer


Descriptive Note : Annual summary rept. 23 Feb 2004-22 Feb 2007


Corporate Author : PENNSYLVANIA UNIV PHILADELPHIA


Personal Author(s) : Keleti, David ; Lemmon, Mark A


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a469536.pdf


Report Date : Mar 2007


Pagination or Media Count : 21


Abstract : Homology (PH) domains are commonly thought of as membrane-targeting modules involved in signaling pathways that bind phosphoinositides (PPIns) with high affinity and specificity. In a recent study of S. cerevisiae, however, the vast majority demonstrated little affinity or specificity for PPIns (Yu et al, 2004). I show comparable results for my selected human PH domains, with only one that is high affinity and PPIns-specific, while the remainder are low to moderate affinity and promiscuous for PPIns. I outline two instances where multipoint contacts (protein-protein and protein-phosphoinositide interactions) may account for specific membrane targeting observed in vivo. First, SH3BP-2 PH was identified as highly specific for the membrane lipid PtdIns(3,4)P2, and targets the host adaptor protein to the membrane (while its SH2 and PR domains bind proteins). Second, FAPP1 and OSBP PH domains possess comparable affinities for Golgi- and plama membrane-enriched PPIns in vitro, although they both localize to the Golgi, and not the plasma membrane in vivo, a likely result of a direct interaction with the Golgi GTPase Arf1 (Godi et al, 2004). I have solved the structure of a member of this PH domain class in complex with PPIns, and suggest reasons for its unique PPIns binding properties. Finally, the drug perifosine was found to selectively target Akt1/PKBalpha PH in vitro, albeit with a relatively low binding affinity.


Descriptors :   *IN VITRO ANALYSIS , *ONCOGENIC VIRUSES , *BREAST CANCER , INTERACTIONS , MOLECULES , PLASMAS(PHYSICS) , TARGETING , IN VIVO ANALYSIS , PH FACTOR , ADAPTERS , MEMBRANES , PROTEINS , TARGETS


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE