Lipid Growth Factor Signaling
The Autotaxin-LPA Signaling Axis
LPA is an extracellular signaling molecule that acts through
multiple G protein-coupled receptors present in numerous cell
types.LPA receptor signaling is implicated in a wide variety of
physiological and pathological processes, ranging from vascular
development to metastasis. The classical LPA receptors stimulate
cell migration and proliferation, and are implicated in cell
transformation and metastasis. Newly identified LPA receptors can
mediate inhibitory responses, which renders the global LPA
signaling picture increasingly complex. One challenge is to
understand how distinct LPA receptors cooperate, to predict the
biological outcome of LPA stimulation in a given cell type.
Autotaxin (ATX) is the major LPA-producing enzyme in plasma and
tissues. We are analyzing the function of autotaxin using multiple
approaches, including structural studies and the development of
mouse models and small-molecule inhibitors. The knockout mouse
revealed an unexpected function for ATX in vascular development.
Furthermore, the structure of ATX revealed novel features, notably
the presence of a deep lipid-binding pocket and a nearby open
tunnel, which we are now further investigating (collaboration A.
Perrakis). Our studies have provided new insights into the mode of
action of ATX, and how it delivers LPA to target cells. Targeting
the ATX-LPA signaling axis may prove a valuable strategy for
inhibiting tumor cell growth and metastasis.