Sphingosine 1-phosphate, lysophosphatidic acid and growth factor signaling and termination

Abstract

Sphingosine 1 phosphate (S1P) and lysophosphatidic acid (LPA) are bioactive lipid phosphates that bind to cell surface G-protein coupled receptors (GPCR) and, in addition, exhibit intracellular actions. We have summarised herein, an important functional interaction between lipid phosphate GPCR and receptor tyrosine kinases (RTK) that enables growth factors to spatially regulate effectors, thereby governing the nature of the biological response. For instance, we describe how the formation of functional complexes between the S1P(1) receptor and PDGFbeta receptor may effectively re-programme platelet-derived growth factor from a mitogenic to a migratory stimulus. This is achieved by integration of RTK- and GPCR-specific signals that results in spatial regulation of a cytoplasmic retained pool of extracellular signal regulated kinase-1/2 linked to myosin light chain kinase, myosin light chain phosphorylation and migration. We therefore suggest that the lipid phosphate receptor is a major determinant in regulating growth factor-dependent biology. Growth factors can also increase S1P inside cells, and we discuss the concept of spatial/temporal aspects of compartmentalised intracellular signaling of S1P in relation to defined interactions between, for instance, sphingosine kinase, phospholipase D1 and lipid phosphate phosphatases and regulation of cell survival.