Phospholipase D in Cell Signaling: From a Myriad of Cell Functions to Cancer Growth and Metastasis

Abstract

Phospholipase D (PLD) enzymes play a double vital role in cells: they maintain the integrity of cellular membranes and they participate in cell signaling including intracellular protein trafficking, cytoskeletal dynamics, cell migration, and cell proliferation. The particular involvement of PLD in cell migration is accomplished: (a) through the actions of its enzymatic product of reaction, phosphatidic acid, and its unique shape-binding role on membrane geometry; (b) through a particular guanine nucleotide exchange factor (GEF) activity (the first of its class assigned to a phospholipase) in the case of the mammalian isoform PLD2; and (c) through protein-protein interactions with a wide network of molecules: Wiskott-Aldrich syndrome protein (WASp), Grb2, ribosomal S6 kinase (S6K), and Rac2. Further, PLD interacts with a variety of kinases (PKC, FES, EGF receptor (EGFR), and JAK3) that are activated by it, or PLD becomes the target substrate. Out of these myriads of functions, PLD is becoming recognized as a major player in cell migration, cell invasion, and cancer metastasis. This is the story of the evolution of PLD from being involved in a large number of seemingly unrelated cellular functions to its most recent role in cancer signaling, a subfield that is expected to grow exponentially.

Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression

“…38). Expression of PLD2 but not of a variant of PLD2 with a reduced catalytic activity (PLD2 Y511F (ref.…”

Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

“…Surprisingly, PA and PLD bind similar proteins, and phosphorylation at tyrosines 169 and 179 in PLD2’s PX domain induces binding to the SH2 domains of Grb2 (Gomez-Cambronero, 2014). In addition, the SH3 domain of PLCγ1 binds the proline-rich motif within the PX domain of PLD2 to enhance epidermal growth factor receptor’s ability to stimulate PLC activity (Jang et al, 2003).…”

Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells

“…PLD2 is mainly localized to the plasma membrane and on the endosomes, and has been reported to regulate both cell motility and membrane trafficking in a variety of cell types (Du et al, 2004; Frohman, 2015). The expression and activity of PLD2 are upregulated in some types of cancer including breast cancer (Bruntz et al, 2014; Gomez-Cambronero, 2014). In addition, increasing PLD2 expression enhanced, whereas inhibition of PLD2 blocked, cancer cell proliferation, invasion and metastasis, in cell lines and a mouse xenograft model (Henkels et al, 2013; Zhang et al, 2014).…”