Phospholipase D1 (PLD1) is an enzyme that in humans is encoded by the PLD1 gene, [5] [6] though analogues are found in plants, fungi, prokaryotes, and even viruses. [7]
Phospholipase D1 (PLD1) is an enzyme that in humans is encoded by the PLD1 gene, [5] [6] though analogues are found in plants, fungi, prokaryotes, and even viruses. [7]
The possibility of PLD1 was first mentioned in 1947 by authors Hanahan and Chaikoff at Berkeley when describing a carrot enzyme that could "[split] choline from phospholipids." [8] PLD was first derived in mammals in 1975 by Saito and Kanfer, who noted its activity in rats. [9] PLD was first cloned from HeLa cell cDNA in 1995, while mammalian PLD1 was first cloned from a rat in 1997. [7]
Phosphatidylcholine (PC)-specific phospholipases D (PLDs) EC 3.1.4.4 catalyze the hydrolysis of PC to produce phosphatidic acid (PA) and choline. A range of agonists acting through G protein-coupled receptors and receptor tyrosine kinases stimulate this hydrolysis. PC-specific PLD activity has been implicated in numerous cellular pathways, including membrane trafficking, signal transduction, platelet coagulation, mitosis, apoptosis, and the creation of cytoplasmic lipid droplets. [6] [7] [10] [11]
PLD1 has been shown to associate at the plasma membrane, late endosome, [12] early endosome, and the Golgi apparatus. [7] [9] There is evidence that PA is able to assist in negative membrane curvature due to its head group being smaller than in many other lipids. [7] One experiment with PLD1 knockout showed a significant reduction in the number of exocytotic fusion events, implying a strong role in exocytosis. [13]
PLD1 may play a role in some cells in the endocytosis of signaling receptors or exocytosis of signaling molecules. For example, one experiment in B cells showed that limiting PLD1 led to significantly reduced endocytosis of the B cell receptor. [12] Another experiment showed that knocking out PLD1 may hinder the ability of mice to secrete catecholamines, molecules that are essential for vesicular communication across the body. [13]
Mammalian PLD1 has several domains for activators, inhibitors, and catalysis, which it shares with PLD2. Domains for both activation and inhibition are referred to as the phox homology (PX) and pleckstrin homology (PH) domains. The catalytic domain consists of two HKD regions, so named for three of the amino acids that are key in catalysis. These domains are conserved across many organisms. [7] [9] There are two splice variants of the protein, PLD1a and PLD1b, but they do not seem to localize any differently. [7]
Alzheimer's disease: PA, which is produced in part by PLD1, seems to be involved in the movement of β-amyloid, which could precede amyloidogenesis. [14]
Cancer: certain rat tumors with dominant negative PLD do not appear to form new colonies or tumors. [7] [14]
Thrombosis: PLD knockout mice appear to have reduced occlusion, thus offsetting thrombosis. [7]
Type II Diabetes: the protein PED/PEA15 is often elevated in type II diabetic patients, thus enhancing PLD1 activity, and in turn impairing insulin. [7]
Phospholipase D1 has been shown to interact with:
ADP-ribosylation factor 6 (ARF6) is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein cargo. ARF6 has specifically been implicated in endocytosis of plasma membrane proteins and also, to a lesser extent, plasma membrane protein recycling.
Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.
Phospholipase C, gamma 1, also known as PLCG1 and PLCgamma1, is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the PLCG1 gene and is part of the PLC superfamily.
ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.
Phospholipase D2 is an enzyme that in humans is encoded by the PLD2 gene.
Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.
ARF GTPase-activating protein GIT1 is an enzyme that in humans is encoded by the GIT1 gene.
Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.
ARF GTPase-activating protein GIT2 is an enzyme that in humans is encoded by the GIT2 gene.
Phosphatidylinositol-glycan-specific phospholipase D is an enzyme that in humans is encoded by the GPLD1 gene.
ADP-ribosylation factor 5 is a protein that in humans is encoded by the ARF5 gene.
ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.
Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2. This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.
ADP-ribosylation factor-like protein 1 is a protein that in humans is encoded by the ARL1 gene.
ADP-ribosylation factor-related protein 1 is a protein that in humans is encoded by the ARFRP1 gene.
GTP-binding protein ARD-1 is a protein that in humans is encoded by the TRIM23 gene.
Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1 is an enzyme that in humans is encoded by the AGAP1 gene.
Arfaptin-1 is a protein that in humans is encoded by the ARFIP1 gene.
