From the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112
In the introduction to "A
Thematic Series on Phospholipases" that appeared about two years ago
(Prescott, S.M. (1997) J. Biol. Chem. 272, 15043) I commented that phospholipids are a reservoir for lipid
mediators that support many intracellular events and that the initial
step leading to their synthesis was activation of a phospholipase. This
series reviews another molecular route to generating, and then shutting
off, lipid-based signals: phosphorylation (or dephosphorylation) of a
lipid. This is a well characterized mechanism for regulating the
function of proteins, and the last decade has seen an explosion of
information about similar processes in regulating lipid messengers. The
first clue was the observation that phosphatidylinositol and its
analogs with phosphates on the inositol ring were substrates for the
addition of another phosphate and that this reaction occurred at the
3-position of inositol, a previously unrecognized target.
This finding led to remarkable insights into signals that
regulate cellular growth and differentiation. This important body of
work is covered in the first paper, "The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function" by Lucia E. Rameh and Lewis
C. Cantley. The kinases, or at least many of them, responsible for this
modification have been identified, their cDNAs cloned, and their
substrate specificity and subcellular location(s) identified. The
phosphoinositide 3-kinases were found early on to be associated with
other proteins, notably receptors for growth factors, and this
observation has progressed to a detailed list of such binding partners
and definition of the regions of the proteins that are essential for
the interactions.
Likewise, the question of how the phospholipid products from the
reaction catalyzed by phosphoinositide 3-kinase(s) alter cell responses
has been extensively studied. Many target proteins have been
identified, and specific sequences that bind the 3-phosphorylated phospholipids have been determined. Rameh and Cantley review this area,
and then it is focused upon by Andrew E. Wurmser, Jonathan D. Gary, and
Scott D. Emr in their article, "Phosphoinositide 3-Kinases and Their
FYVE Domain-containing Effectors as Regulators of Vacuolar/Lysosomal
Membrane Trafficking Patterns." One particularly productive area of
investigation is featured in this review, i.e. the
definition of the essential role of these lipids in membrane trafficking, a subject that has been particularly well served by
genetic approaches in yeast.
The description of the consequences of adding phosphate(s) to
phosphatidylinositol is continued in the review,
"Phosphatidylinositol Phosphate Kinases, a Multifaceted Family of
Signaling Enzymes" by Richard A. Anderson, Igor V. Boronenkov, Scott
D. Doughman, Jeannette Kunz, and Joost C. Loijens. It has been known
for many years that phosphatidylinositol could be converted to singly
and doubly phosphorylated forms with the additions at the 4- and
5-positions of the inositol; in fact, such products are found as trace
components of cellular membranes. The recent identification of the
kinases that catalyze these reactions has both explained the usual
synthetic pathway for these membrane constituents and, as with the
3-kinase story, led to the observation that the synthesis of these
lipids was involved in many types of cellular signaling. As with the 3-kinases, these enzymes are found in complexes with other signaling proteins, a general theme that has emerged in studies of lipid kinases
and phosphatases, just as with protein kinases and phosphatases.
The study of inositol phosphatases began as an effort to define
one of the off switches in signaling initiated by the
hydrolysis of phosphoinositides; this is one of the
phospholipase-initiated pathways mentioned above, and when
phosphatidylinositol P2 is cleaved by a phospholipase C the
water-soluble product, inositol trisphosphate, is a signal to raise the
intracellular calcium concentration. The removal of the 5-phosphate
abolishes the signal and calcium declines. After members of this
phosphatase family were identified it subsequently was found that some
of them also could catalyze the removal of phosphate from the
phospholipids, a completely unexpected finding. This property has been
implicated in the tumor-suppressing ability of one of the inositol
phosphatases, PTEN. This rapidly evolving field is reviewed by Philip
W. Majerus, Marina V. Kisseleva, and F. Anderson Norris in their
article "The Role of Phosphatases in Inositol Signaling Reactions."
Another signal from the phosphatidylinositol signaling cycle that
needs to be shut off is diacylglycerol, the other product of the
phospholipase C reaction. This neutral lipid is present only in very
low amounts in normal, resting cells but rises in response to many
types of stimuli and is elevated persistently in many transformed
cells. Its major action is to activate members of the protein kinase C
family, which have diverse effects on cell growth, differentiation, and
other responses. The major route for lowering the transiently elevated
diacylglycerol is by conversion to phosphatidic acid, a reaction that
adds phosphate to the lipid. This is catalyzed by a family of kinases
that Matthew K. Topham and I review in "Mammalian Diacylglycerol
Kinases, a Family of Lipid Kinases with Signaling Functions." As with
the kinases and phosphatases that modify phosphatidylinositol, the
diacylglycerol kinases are a diverse group.
Two themes run through these reviews of enzymes that add and remove
phosphate from lipids. First, they are found in complexes with other
signaling proteins including protein kinases and phosphatases, G
proteins, and each other. Second, although they all were initially assumed to be part of events localized to the plasma membrane and
nearby cytoplasm, they all have additionally been found to be in the
nucleus, where they participate in what appears to be a parallel
signaling system. Both of these themes will attract intense interest in
the next few years as the functional significance is
dissected.
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Fig. 1.
This figure is a highly stylized version of
the signaling pathways that will be reviewed in the series.
PI denotes phosphatidylinositol, and PIP,
PIP2, and PIP3 refer to
compounds derived by the addition of phosphates to the inositol ring at
the 3-, 4-, and 5-positions in various combinations. The details of
these complex pathways will be covered in the individual reviews, but
it is important to note that the individual compounds have specific
downstream actions that depend on where on the ring the phosphorylation
occurs. DG, diacylglycerol; PA, phosphatidic
acid; and P'ase, phosphatase;
IPx, inositol with 1 or more phosphates;
I, inositol; P, phosphate.
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* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999.