From the Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84112
Membranes are an essential component of
all cells since without them the cell cannot assert its identity or
subdivide its functions into specialized compartments. Phospholipids
are the major building block of membranes, which has made them an
important target for study. In addition to this structural role, much
work over the last 25 years has revealed that phospholipids serve
another crucial function in eukaryotic, particularly mammalian, cells; they are a reservoir from which cells generate intracellular and intercellular messengers. These range from oxidized fatty acids (the
eicosanoids and their relatives) to unusual phospholipids (platelet-activating factor and lysophosphatidic acid) to lipids previously known to be intermediates in phospholipid synthesis (diacylglycerol and phosphatidic acid). These signaling mechanisms have
attracted broad interest since lipid messengers have been implicated in
fundamental cellular responses including growth, differentiation,
adhesion, migration, secretion, and apoptosis. From a medical
perspective, they have been accused of promoting inflammation,
thrombosis, cancer, asthma, and other ills. All of the pathways that
lead to the generation of these second messengers share one
property-they are initiated by a phospholipase; thus, it is not
surprising that attention has been focused on them.
The study of phospholipases has a long, elegant history beginning with
experiments on venoms and toxins, which often are rich sources, and on
the role of these enzymes in the digestion of fats. The role of
phospholipases in generating lipid signals has been recognized for many
years, but a characterization of the molecular details has been
achieved only recently as phospholipases have been purified and
cDNAs encoding them have been cloned. This has been a hard road to
travel; the phospholipases involved in signaling are present only in
low amounts, and they often are difficult to keep in solution.
Moreover, their substrates are hydrophobic, and the phospholipases
often prefer the substrates to be structured rather than monomeric,
which complicates both the assay and the analysis. We now are realizing
the benefit of the effort; multiple pure phospholipases are available
and their structure, function, and regulation can be assessed using the most powerful methods. This series of reviews describes the
state-of-the-art for several classes of phospholipases involved in
signaling (Fig. 1). The first article in the series
addresses the phospholipases C that are the key step in the
phosphatidylinositol pathway, which provides intracellular signals that
regulate calcium and protein kinase C. The subsequent article reviews
recent studies on phospholipase D including its regulation. Then, a
series within the series tackles phospholipases A2, which
have proven to be quite diverse. The reviews are: "Regulation of
Phosphoinositide-specific Phospholipase C Isozymes" by Sue Goo Ree
and Yun Soo Bae; "New Developments in Phospholipase D" by John H. Exton; "Function and Inhibition of Intracellular Calcium-independent
Phospholipase A2" by Jesús Balsinde and Edward A. Dennis; "Properties and Regulation of Cytosolic Phospholipase
A2" by Christina C. Leslie; "A Reassessment of the Low
Molecular Weight Phospholipase A2 Gene Family in Mammals" by Jay A. Tischfield; and "Platelet-activating Factor
Acetylhydrolases" by Diana M. Stafforini, Thomas M. McIntyre, Guy A. Zimmerman, and Stephen M. Prescott.
Fig. 1.