Identification of Novel Molecular Targets for Pleckstrin Homology (PH) Domains Found in Oncogenes Implicated in Breast Cancer
Abstract
Plecktrin Homology (PR) 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 PI(4,5)P2 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). All human PH domains were subdivided into 66 phylogenetic classes, and a "class representative" selected for in vitro phosphoinositide binding (21 completed) and in vivo localization studies (43 completed). The results are comparable to the yeast study, with only one confirmed high affinity and PI(4,5)P2-specific and several moderate affinity and promiscuous PH domains, while the remainder are low affinity and promiscuous. As in yeast, several low-to-moderate affinity and promiscuous PR domains showed plasma membrane or punctate localization. Two PR domains of this class possess comparable affinities for Golgi- and plasma membrane-enriched phosphoinositides in vitro, although they both localize to the Golgi, not the plasma membrane in vivo. Additionally: * A moderate affinity, PI(3,4)P2-specific PR domain was identified. An alkylphospholipid drug was found to selectively target a PH domain in vitro.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2005
- Accession Number
- ADA435560
Entities
People
- David Keleti
Organizations
- University of Pennsylvania