Lipid phosphate phosphatases and related proteins: Signaling functions in development, cell division, and cancer

Abstract

Lipid phosphates initiate key signaling cascades in cell activation. Lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are produced by activated platelets. LPA is also formed from circulating lysophosphatidylcholine by autotaxin, a protein involved tumor progression and metastasis. Extracellular LPA and S1P stimulate families of G-protein coupled receptors that elicit diverse responses. LPA is involved in wound repair and tumor growth. Exogenous S1P is a potent stimulator of angiogenesis, a process vital in development, tissue repair and the growth of aggressive tumors. Inside the cell, phosphatidate (PA), ceramide 1-phosphate (C1P), LPA, and S1P act as signaling molecules with distinct functions including the stimulation of cell division, cytoskeletal rearrangement, Ca(2+) transients, and membrane movement. These observations imply that phosphatases that degrade lipid phosphates on the cell surface, or inside the cell, regulate cell signaling under physiological and pathological conditions. This occurs through attenuation of signaling by the lipid phosphates and by the production of bioactive products (diacylglycerol, ceramide, and sphingosine). Three lipid phosphate phosphatases (LPPs) and a splice variant dephosphorylate LPA, PA, CIP, and S1P. Two S1P phosphatases (SPPs) act specifically on S1P. In addition, there is family of four LPP-related proteins (LPRs, or plasticity-related genes, PRGs). PRG-1 expression in neurons has been reported to increase extracellular LPA breakdown and attenuate LPA-induced axonal retraction. It is unclear whether the LRPs dephosphorylate LPA directly, stimulate LPP activity, or bind LPA and S1P. Also, the importance of extra- versus intra-cellular actions of the LPPs and SPPs, and the individual roles of different isoforms is not firmly established. Understanding the functions and regulation of the LPPs, SPPs and related proteins will hopefully contribute to interventions to correct dysfunctions in conditions such as wound repair, inflammation, angiogenesis, tumor growth, and metastasis.

A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase

“…Therefore, membrane recruitment of lipins could be a major regulatory step during membrane biogenesis or energy storage in lipid droplets. Mammalian lipins respond to several stimuli: Fatty acids cause translocation of a soluble PAP activity on microsomal membranes (26), whereas insulin causes phosphorylation and increase of the soluble pool of lipin 1 in 3T3-L1 adipocytes (27). Whether, as in yeast, these changes require a membrane-bound receptor, such as the mammalian Nem1p orthologue Dullard (28), is not known.…”

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

“…LPA is a potent activator of platelet aggregation and it stimulates the division and migration of fibroblasts, vascular smooth muscle cells, endothelial cells and keratinocytes [39] . Increased ATX activity is found in blister fluid where local production of LPA promotes re-epithelialization [40] .…”

“…The production of inflammatory cytokines, such as in damaged and inflamed tissue, is a signal for increased ATX expression and LPA production to heal the wound [39,56] . If this process is successful and inflammation subsides, then LPA produced by ATX feeds back and blocks further ATX production.…”

“…The initial relation of ATX/LPA signaling with melanoma cells resulted in much of the early research into ATX being concentrated in the cancer field [39,[57][58][59][60][61][62][63][64][65] . LPA increases vascular endothelial growth factor (VEGF) production, which stimulates angiogenesis [66] , a process necessary for tumor progression.…”

“…This work replicated our S-phase cell cycle findings, and further showed LPP2 to be negatively regulated by p53, a major tumor suppressor [122] . More information on the LPPs and related proteins can be obtained by reference to other reviews [10,39,110,123] .…”