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| PX: Phox homology (PX) domain; PH: Pleckstrin homology (PH) domain; Loop: Loop region; I, II, III, IV: conserved regions I, II, III, and IV; The red arrow indicates the difference between PLD1a and PLD1b. |
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Description | PLD1 (MW: about 120 kDa) contains the several conserved domains/regions (Hammond et al., 1995). PLD superfamily has a well-conserved HKD motif (HXK[X]4D[X]6GSXN), which is in conserved regions II and IV that mediate PLD enzymatic activity. In addition, the PX and PH domains are known to be implicated in interactions with other proteins and phosphoinositide 4,5-bisphosphate (PtdIns (4,5)P2), respectively (Sung et al., 1999). Recently, the PX and PH domains of PLD have been reported to be the core binding regions of PLD and to mediate its functions. For example, dynamin and μ2 showed the effects on EGFR-mediated endocytosis via R128/R197 of the PLD1-PX domain and R304 of the PLD1-PH domain, respectively (Lee et al., 2006; Lee et al., 2009b). Also, PLCgamma and munc18 can interact with the P161/P164 of the PLD1-PX domain and the C-terminal region (184~212 residues) of the PLD1-PX domain, respectively (Jang et al., 2003; Lee et al., 2004). These interactions occur in an EGF-dependent manner and contribute to the regulation of PLD activity. Furthermore, PKCalpha can phosphorylate the T147 of the PLD1-PX domain to increase PLD activity (Kim et al., 1999). In addition, to protein interactions, these domains can interact with phospholipids. Recently, it has been reported that phosphoinositide 3,4,5-bisphosphate (PtdIns (3,4,5)P3 interacts with the R179 of the PLD1-PX domain and can stimulate PLD activity (Lee et al., 2005). Phosphatidic acid-(PA) can also bind to PLD via a secondary lipid-binding pocket residue (R158) in the PLD1-PX domain (Stahelin et al., 2004). In addition, PLD1-PH domain also interacts with phosphoinositide 4,5-bisphosphate (PtdIns (4,5)P2 (Hodgkin et al., 2000). It has been reported that this interaction can regulate PLD activity and localization. |
Expression | PLD1 is ubiquitously expressed in a variety of tissues including brain, lung, heart, liver, adipose tissue, and spleen (Meier et al., 1999). The expression level of PLD1 is elevated in several cancer cells (Noh et al., 2000; Buchanan et al., 2005). |
Localisation | It is believed that PLD1 is primarily localized in perinuclear regions, such as, endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles (Jenkins et al., 2005). Several reports have suggested that PLD1 is also localized in endosomes (early, late, and recycling) and lysomes (Toda et al., 1999; Hughes et al., 2001; Du et al., 2003). Furthermore, PLD1 can translocate to the plasma membrane in a signal-dependent manner (Brown et al., 1998), and can be localized in specialized region (caveolae) of the plasma membrane. The C240/C241 residues of PLD1 are palmitoylated to localize at caveolae, and this localization is important for mediating EGF signaling (Han et al., 2002). Recently, it was reported that PLD1 also has nuclear roles (Gayral et al., 2006). |
Function | PLD1 is a phospholipid-hydrolyzing enzyme that can catalyze phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline. PA can function as a second messenger and can be converted to other biomolecules, such as, LPA and DAG (Jenkins et al., 2005). PA can interact with a variety of molecules to recruit it to the membrane. For example, PA binds to mTOR-FRB domain and regulates its cell growth signaling activity (Fang et al., 2001), and can interact with PtdIns(4)P 5-Kinase (Honda et al., 1999); this latter interaction can modulate the generation of PtdIns(4,5)P2. Recently, it was been reported that PA can translocate SOS to the plasma membrane to mediate EGF signaling (Zhao et al., 2007). PLD can mediate many cellular phenomena, such as, proliferation, vesicle trafficking, cytoskeleton reorganization, and differentiation, and recently, Elvers et al. after a study on PLD1 knockout mice, reported that PLD1 can modulate thrombus formation via platelet aggregation (Elvers et al., 2010). Proliferation PLD can be activated by a variety of mitogenic signals - epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin, growth hormones, lysophosphatidic acid (LPA), and spingosine 1-phosphate - all of which can directly bind with G-protein coupled receptors (GPCR) and receptor-tyrosine kinases (RTK). PLD activation via mitogenic signals can induce cell proliferation, cell survival, the suppression of cell cycle arrest, and the prevention of apoptosis (Foster et al., 2003; Lee et al., 2009a; Su et al., 2009). Furthermore, elevated PLD activity has been shown to transform cells (Buchanan et al., 2005). Vesicle trafficking It has been reported that PLD is critically involved in vesicle formation and trafficking, such as, in endocytosis, exocytosis, and vesicle formation from the trans-Golgi network (Cazzolli et al., 2006). PLD-derived PA generation can recruit downstream molecules (PtdIns(4)P 5-Kinase) that are involved in vesicle fusion and mediate the inner membrane curvature (Jenkins et al., 2005). Many reports have suggested that PA generation by PLD can contribute to exocytosis (immune cell degranulation, neurotransmitter secretion, and EGF secretion) in various cell lines, such as, mast cells, adipocytes, and neuroendocrine cells. Furthermore, endocytosis (receptor mediated endocytosis and phagocytosis) also depends on PA generation by PLD (Humeau et al., 2001; Hughes et al., 2004; Huang et al., 2005; Peng et al., 2005). Recently, we have been suggested that PLD protein can increase the GTPase activity of dynamin, which is important for endocytosis, and that PLD itself, and not PA, can increase EGFR endocytosis (Lee et al., 2006). Cytoskeletal reorganization PA generation by PLD activation has been shown to be a key regulator of cytoskeletal dynamics to induce cell adhesion, spreading, and migration. PLD can be activated by kinases (PKC and PtdIns(4)P 5-Kinase) and small G proteins (Rho, Rac, cdc42, Arf, and Ral) that mediate signaling essentially required for cytoskeletal reorganization (Rudge et al., 2009). Moreover, PLD-derived PA can translocate GTP-Rac to the plasma membrane and induce integrin-mediated cell spreading (Chae et al., 2008). Differentiation PLD appears to be involved in the differentiation of various cells. Prolonged PA generation by PLD activation is correlated with the differentiation of keratinocytes (Jung et al., 1999), and the PLD isozyme expression levels are increased during granulocytic differentiation (Di Fulvio et al., 2005). PLD is well known to have an essential role during neuronal cell differentiation (Kanaho et al., 2009). Recently, Yoon et al reported that PLD can induce myoblast differentiation via the secretion of IGF2 in an autocrine manner (Yoon et al., 2008). |
Homology | A blast search produced the following results: 85% sequence identity in Mus musculus. 87% sequence identity in Rattus norvegicus. 47% sequence identity in C. elegans. 56% sequence identity with PLD2 of Homo sapiens. |
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