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).