Proliferative signaling Multiple extracellular mitogenic signals, such as, EGF, platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) can activate PLD2 to generate PA (Lee et al., 2009; Park et al., 2012). Specially, PLD2 is known to be implicated in EGF-mediated cell proliferation (Ahn et al., 2003). Furthermore, it has been well established that EGF signaling can be regulated via dynamic interactions between PLD2 (PA) and its binding partners (Lee et al., 2009). In addition, EGF can induce dissociation between PLD2 and munc-18 to activate PLD2 (Lee et al., 2004). Activated EGFR can recruit PLCγ to EGFR complex, and PLD2 can activate PLCγ which can generate IP3 and DAG for the activation of PKC (Jang et al., 2003). PLCγ can also serve as a GEF for dynamin (Choi et al., 2004). GTP-loaded dynamin and PKC can activate PLD2, which can act as a GAP for dynamin to potentiate EGFR endocytosis (Park et al., 2004; Lee et al., 2006). PA, generated by PLD activation, can recruit SOS to the plasma membrane. SOS acting as a GEF for Ras can activate the MAP kinase cascade (a key proliferative signaling pathway) and eventually induce cell proliferation and transformation (Zhao et al., 2007).
Cell growth signaling Cells regulate cellular homeostasis by using extracellular nutrients and growth signals, and malfunctions in this process cause severe diseases, such as, cancer and diabetes. PLD2 acts as a key regulator of growth signaling mainly via the control of the mammalian target of rapamycin (mTOR), which is a key target for cancer treatment (Ha et al., 2006). Both PLD2 and PA can affect mTor signaling. PA can directly interact with the FRB domain of mTOR and activate mTOR (Toschi et al., 2009). Rapamycin (an anti-cancer drug) can inhibit mTOR activation by competing with PA for mTOR (Fang et al., 2001). In addition, PLD can bind Raptor, which complex strongly with mTOR, and interact with Rheb (an upstream GTPase of mTOR) in a GTP-dependent manner (Sun et al., 2008). Furthermore, these interactions are required for the activation of mTOR complex and the mediation of growth signaling.
Vesicle trafficking (endocytosis, and exocytosis) PLD is known to be implicated in vesicle trafficking, such as, in intracellular vesicle trafficking, endocytosis, and exocytosis (Jones et al., 1999). In addition, PA generation by PLD has been reported to be involved in vesicle fusion by mediating inner membrane curvature (Jenkins and Frohman, 2005). Many reports have suggested that PLD1 is essentially involved in secretion and exocytosis (Vitale et al., 2001; Vitale et al., 2002), but recently, PLD2 was also found to be required for exocytosis. For example, Lee et al. reported that PLD2 is critically involved in insulin secretion by EGF in primary pancreatic islets and in a pancreatic beta cell line (Lee et al., 2008b). Also, PLD2 can induce angiotensin II-mediated aldosterone secretion from adrenal glomerulosa cells (Qin et al., 2010), and in addition to exocytosis, PLD2 is a well known essential mediator of receptor-mediated endocytosis and phagocytosis (Shen et al., 2001; Iyer et al., 2004). Furthermore, the overexpression of PLD2 wild-type can increase EGFR endocytosis, whereas the catalytic inactive PLD2 mutant does not (Shen et al., 2001). Moreover, mu-opioid receptor endocytosis and constitutive metabotropic glutamate receptor endocytosis can be affected by PLD2 activation (Koch et al., 2003; Bhattacharya et al., 2004). PLD2 activity can also regulate the phagocytosis of complement-opsonized zymosan in macrophages (Iyer et al., 2004). Many authors have suggested that PA generation by PLD2 activation is critically implicated in endocytosis and exocytosis. However, recently, it was reported that PLD2 itself, and not PLD2 activity, regulates endocytosis and phagocytosis (Lee et al., 2006; Mahankali et al., 2011). As we addressed above, PLD2 has GAP and GEF functions (PLD2-PX domain, which acts as a GAP for dynamin, and a PLD2-PH domain, which acts as a GEF for Rac2). Furthermore, the PLD2-GAP function for dynamin can accelerate EGF-mediated EGFR endocytosis and the PLD2-GEF function for Rac2 can increase phagocytosis in RAW264.7 macrophages.
Cytoskeletal rearrangement Cells can undertake cytoskeletal changes by utilizing the dynamics of actin and tubulin (Berepiki et al., 2011; de Forges et al., 2012). These changes play a vital role in mediating a variety of cellular processes, such as, adhesion, spreading, migration, phagocytosis, and cytokinesis (Hynes, 2002). These processes are essential for pathophysiological functions, such as, organ morphogenesis and metastasis (Fletcher and Mullins, 2010). Several authors have suggested that PLD2 has a close relationship with cytoskeletal dynamics. For example, PLD2 can directly interact with kinases (PKC and PtdIns(4)P 5-Kinase) and small G proteins (Ral, Arf1, Arf4, and Arf6) that modulate cytoskeletal dynamics (Jang et al., 2012). Furthermore, cytoskeletal proteins, such as, actin and tubulin, can direct bind to PLD2 and inhibit its activity (Chae et al., 2005). Also, PA generation by PLD2 activation can activate PtdIns(4)P 5-Kinase to generate PtdIns(4,5)P2, which is involved in actin polymerization (Moritz et al., 1992). Also, integrin-mediated PA generation by PLD can recruit GTP-loaded Rac1 to the plasma membrane and be involved in activating Rac1 to mediate cell spreading and migration (Chae et al., 2008). Recently, in addition to PA generation by PLD2 activation, PLD2 (acting as a GEF) was found to be critically implicated in actin dynamics, for example, PLD2 can serve as a GEF for RhoA and Rac2 (Jeon et al., 2011; Mahankali et al., 2011). Furthermore, it has been reported that PLD2, acting as a GEF for RhoA, participates in LPA-mediated stress fiber formation and that PLD2, acting as a GEF for Rac2, is important for the mediations of migration and phagocytosis.
NCBI: 5338 MIM: 602384 HGNC: 9068 Ensembl: ENSG00000129219
dbSNP: 5338 ClinVar: 5338 TCGA: ENSG00000129219 COSMIC: PLD2
Chang Sup Lee ; Sung Ho Ryu
PLD2 (phospholipase D2)
Atlas Genet Cytogenet Oncol Haematol. 2013-04-01
Online version: http://atlasgeneticsoncology.org/gene/43849/pld2