Signalling roles of mammalian phospholipase D1 and D2

Abstract

Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidate (PA) and choline. PLD activity in mammalian cells is low and is transiently stimulated upon activation by G-protein-coupled and receptor tyrosine kinase cell surface receptors. Two mammalian PLD enzymes (PLD1 and PLD2) have been cloned and their intracellular regulators identified as ARF and Rho proteins, protein kinase Calpha as well as the lipid, phosphatidylinositol bisphosphate (PIP2). I discuss the regulation of these enzymes by cell surface receptors, their cellular localisation and the potential function of PA as a second messenger. Evidence is presented for a role of PA in regulating the lipid kinase activity of PIP 5-kinase, an enzyme that synthesises PIP2. A signalling role of phospholipase D via PA and indirectly via PIP2 in regulating membrane traffic and actin dynamics is indicated by the available data.

Trp-Lys-Tyr-Met-Val-Met stimulates phagocytosis via phospho-lipase D-dependent signaling in mouse dendritic cells

“…The result suggests that PLD activation by WKYMVM is essential for the phagocytic activity in the DCs. Since PA generation is the primary consequence of PLD activation (Lennartz, 1999;Cockcroft, 2001), investigation on the effect of the exogenous addition of PA on the phagocytic activity of DC2.4 cells was carried out. The phagocytic activity in the DC2.4 cells was indeed enhanced by the exogenously added PA (Figure 7B), supporting the hypothesis that PLD activation is necessary for the phagocytic activity in DC2.4 cells.…”

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

“…Little is known about the regulation of this isoform, but it does not appear to be affected by small monomeric GTPases. In the absence of further evidence, some workers have suggested that the purified activity may have been related to PLD2 (40). Two related polyphosphoinositolactivated PLD isoforms have been cloned on the basis of yeast PLD sequences (262,266) and are known as PLD1 (120 kDa) (81, 82, 122, 187) and PLD2 (106 kDa) (43,130).…”

“…In the presence of PIP 2 or PIP 3 , PLD1a and PLD1b are activated by a number of small GTPases, including ADPribosylation factor (ARF) family members, Rho family members (RhoA, Rac, and Cdc42), Ral I and by PKCs, particularly PKC-␣ and PKC-␤ (61,69,81,96,113,139,140). Brefeldin A, a fungal metabolite that interferes with ARF GDP/GTP exchange, inhibits PLD1 activation and certain forms of vesicular trafficking (40,113). Interestingly, phorbol ester stimulation of PLD1 in the presence of PIP 2 or PIP 3 does not require ATP but does require the NH 2 -terminal 168 amino acids (hence known as the phorbol ester-binding domain).…”

“…A number of other proteins, including the 36-kDa ganglioside G m2 activator protein (required for metabolism of G m2 to G m3 ), have also been implicated in PLD1 regulation (217). PLD1 can be modified by palmitoylation and through phosphorylation by PKC and other kinases, for example, the Rho-dependent Rho kinase, although the effects on activity appear variable (40,128,140,277).…”

The elucidation of novel SH2 binding sites on PLD2

“…Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate phosphatidic acid (PA), a second messenger, and choline (Exton, 1998;Cockcroft, 2001). Two main products of PLD genes have been described: PLD1 and PLD2 Park et al, 1997;Lopez et al, 1998;Sung et al, 1999), as well as their regulators (Powner and Wakelam, 2002).…”