Seminar

Phospholipase D (PLD) Cell Signaling in Cancer, Inflammation and Heart Ischemia

Prof. Julian G. Cambronero

Phosphatidic acid (PA) is a “master regulator” in the cell, as it sits at the center of all phospholipid metabolism necessary for cellular membranes architecture, as well as being a key signaling molecule with mitogenic properties and a leukocyte chemoattractant (motogen). PA’s concentration in the cell is finely regulated because its involvement in cell functions is very broad. One of the enzymes that regulate the concentration of PA is phospholipase D (PLD) that breaks down phosphatidylcholine from cell membranes and intracellular membranes, into PA and choline. In mammalian cells, the isoforms PLD1 and PLD2 participate in key cell signaling events, including intracellular protein trafficking, cytoskeletal dynamics, cell migration and cell proliferation. We will concentrate on the biology of the mammalian isoform PLD2, describing protein-protein interactions with a wide network of molecules: WASp, Grb2, Ribosomal S6 Kinase, Rac2 and the tyrosine kinases Fes, JAK and EGFR. PLD2 bears also a Guanine Exchange Factor (GEF) activity that is crucial for its role in actin polymerization and cell migration. The regulation of PLD2 by a set of micro-RNAs, as well as the transcription factors Slug/Snail in relation to breast cancer cell invasion and lung metastasis progression will be also discussed. Additionally, the role of PLD1 and PLD2 (and possibly PLD6) isoforms in heart ischemia/reperfusion injury and the aggravating role of leukocytes infiltrating into the injured heart will be presented. PLD is becoming recognized as a major player in the molecular biology of cell migration, as it has roles in two different but important human conditions: cancer metastasis and cardiovascular disease.