Mechanisms of Lysolipid Phosphate Effects on Cellular Survival and Proliferation

Abstract

The specificity of cellular effects of lysolipid phosphate (LLP) growth factors is determined by binding to endothelial differentiation gene‐encoded G protein‐coupled receptors (EDG Rs), which transduce diverse proliferative and effector signals. The primary determinants of cellular responses to LLPs are the generative and biodegradative events, which establish steady‐state concentrations of each LLP at cell surfaces, and the relative frequency of expression of each EDG R. There are major differences among types of cells in the net effective generation of the LLPs, lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P), and in their profile of expression of EDG Rs. The less well characterized secondary determinants of cellular specificity of LLPs are high‐affinity binding proteins with carrier and cell‐presentation functions, cell‐selective regulators of expression of EDG Rs, and cellular factors that govern coupling of EDG Rs to G protein transductional pathways. The roles of components of the LLP‐EDG R system in normal physiology and disease processes will be definitively elucidated only after development of animal models with biologically meaningful alterations in genes encoding EDG Rs and the discovery of potent and selective pharmacological probes.

GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis

“…These fi ndings all support the notion that LPA and PA can serve as critical factors in initiating adipogenic program, independent of their roles as triglyceride synthetic precursors. Consistent with this notion, the role of LPA, PA, and their downstream products, such as phospholipids, in regulating cell differentiation and growth has been well documented ( 23,24 ). Our transcriptional profi ling data indicate that both GPAT3 and GPAT4 transcripts are expressed at high levels in monocytes, macrophage, and certain myeloid cells (J. Cao et al, unpublished observations); it may not be an exaggeration to speculate that GPAT3 and/or GPAT4 are involved in producing increased levels of LPA and PA in activated infl ammatory cells.…”

Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

“…Since PTX-treatment failed to have any effect on LPA-stimulated proliferation of Ga 12 WT-NIH3T3 cells (number of cells in Ga 12 WT þ LPA ¼ 16.070.5 Â 10 5 compared to 13.671.1 Â 10 5 in Ga 12 WT þ LPA þ PTX group), it is more likely that the LPAR coupled to Ga 12 in stimulating mitogenic response is LPA 2 -receptor. The observation that the increased expression of LPA 1 induces apoptosis (Furui et al, 1999), whereas the expression of LPA 2 promotes the proliferation of ovarian cancer cell lines (Goetzl et al, 1999) further substantiates such pairing of LPA 2 receptor and Ga 12 . This conclusion gains more significance in light of the observation that LPA 2 is one of the receptors whose expression is amplified in certain types of cancers (Mills and Moolenaar, 2003).…”

Bcl10 and Malt1 control lysophosphatidic acid-induced NF-κB activation and cytokine production

“…Stimulation of tumor cells with LPA induces cell proliferation (34), cell survival, and drug resistance (35,36) and promotes cell motility and invasion (37,38) through still-undefined signaling pathways. Aberrant NF-B signaling can mediate all these cellular outcomes (2).…”