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

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Annual summary 23 Feb 2005-22 Feb 2006

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Plecktrin Homology PH domains are commonly thought of as membrane-targeting modules involved in signaling pathways that bind phosphoinositides with high affinity and specificity. In a recent study of all PH domains in S. cerevisiae, only one bound Pl4,5P2 with high affinity and specificity, while another six bound 3- phosphoinositides with moderate affinity and promiscuity the remainder showed little or no affinity or specificity for phosphoinositides Yu et al, 2004. The results of our human PH domain sudy thus far are comparable, with only one confirmed high affinity and Pl4,5P2-specific and several moderate affinity and promiscuous PH domains, while the remainder are low affinity and promiscuous for phosphoinositides. Two PH domains of the moderate affinity and promiscuous class those of FAPPI and OSBP possess comparable affinities for Golgi- and plama membrane-enriched phosphoinositides in vitro, although they both localize to the Golgi, not the plasma membrane in vivo. One reason for this in vivo selectivity appears to be the result of a direct interaction with the Golgi small GTPase Arf1. Moreover, the strong binding affinity of these PH domains for the monophosphoinositide Ptdlns4P versus the diphosphoinositide Ptdlns4,5P2 also suggests an additional phosphoinositide determinant that is currently under investigation.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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