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.
Highlights
The two best characterized mammalian isoforms are PLD1 and PLD2 [5,6,7,8]
A unique characteristic of PLD2 is that it possesses guanine nucleotide exchange factor (GEF) activity for the small GTPases Rac2 and Rho (9 –11) (Fig. 2)
Phospholipase D (PLD) is necessary for normal maintenance of cellular or intracellular membranes [2, 3], and it participates in several physiological cellular functions, such as intracellular protein trafficking, cytoskeletal dynamics, membrane remodeling, and cell proliferation in mammalian cells and meiotic division and sporulation in yeast [4]
Summary
The two best characterized mammalian isoforms are PLD1 and PLD2 [5,6,7,8]. Their genes share about 50% homology including two highly conserved phosphatidyltransferase HKD catalytic motifs that are requisite for catalytic activity. The biggest dilemma concerning the function of PLD is the lack of clarity over a PA binding site on target proteins and understanding of the mechanism of downstream action This is concerning given the plethora of PA-binding proteins that have been identified. Authors suggested a complex regulation patterns between PLD, PA, and their binding partners This paucity of intersection indicates that PLD is an enzyme that cannot be confined to the sole actions derived from its enzymatic activity and, as I will discuss later, the protein-protein interactions involving the whole PLD or parts of the PLD molecular are central to PLD signaling, in cell migration. With the discovery of the GEF catalytic site, it is possible to use lipase-inactive or GEF-inactive mutants to determine lipase or GEF-mediated functions [11]
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