PostDoc Fellowship: Tao Wu Molecular Interactions Regulating Autotaxin/LysoPhospholipase D Activity and Function

  • Morris, Andrew (PI)
  • Wu, Tao (CoI)

Grants and Contracts Details

Description

Autotaxin (ATX) is a secreted lysophospholipase D enzyme that generates the bioactive lipid mediator lysophosphatidic acid (LPA). In the cardiovascular system, genetic and pharmacological evidence identify LPA as a candidate regulator of blood pressure, thrombosis and inflammation through actions on selective G-protein coupled receptors expressed on platelets, vascular smooth muscle cells and vascular endothelial cells. Although studies using ATX -/+ mice and recently developed potent ATX inhibitors clearly establish a role for this enzyme in maintaining systemic circulating plasma LPA levels in the micromolar range, mechanisms by which ATX activity is regulated to produce cell-specific LPA signaling responses are poorly understood. Evidence obtained by ourselves and others indicates that recruitment of ATX to the surface of target cells through interactions with membrane lipids, integrin or scavenger receptors could be a critical determinant of localized LPA signaling. Similarly, while catalytic activity of isolated ATX is low the ability of this enzyme to promote dramatic signaling responses in isolated cells implies that these interactions may result in significant up regulation of enzyme activity. These findings support the broad hypothesis of our research which is that cell-surface recruitment of ATX is vital for LPA synthesis and signaling. The long term goal of our research is to understand the structural basis and biological significance of interactions between ATX and cell surface receptors and lipids responsible for localized production of LPA and to determine the effect of these interactions on ATX activity. These questions will be addressed by pursuing three specific aims. 1. To identify structural determinants in ATX that are responsible for binding interactions with cell surface integrin and scavenger receptors and model membranes. 2. To compare biological activity of membrane bound and membrane tethered variants of ATX. 3. To determine how inter-domain interactions regulate ATX activity. ATX is an attractive target for perturbation of LPA signaling as a strategy for amelioration of vascular injury responses and thrombosis. Development of a molecular level understanding of how ATX activity is localized and controlled is a critical first step in this process.
StatusFinished
Effective start/end date7/1/106/30/12

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