From the Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
Phosphoinositide 3-kinases (PI
3-Ks)1 are a subfamily of
lipid kinases that catalyze the addition of a phosphate molecule
specifically to the 3-position of the inositol ring of
phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all
phosphoinositides (PI), constitutes less than 10% of the total
lipid in eukaryotic cell membranes (Fig.
1). Approximately 5% of cellular PI is
phosphorylated at the 4-position (PtdIns-4-P), and another 5% is
phosphorylated at both the 4- and 5-positions
(PtdIns-4,5-P2). However, less than 0.25% of the total
inositol-containing lipids are phosphorylated at the 3-position,
consistent with the idea that these lipids exert specific regulatory
functions inside the cell, as opposed to a structural function. To
date, nine members of the PI 3-K family have been isolated from
mammalian cells. They are grouped, as suggested by Domin and Waterfield
(1), into three classes according to the molecules that they
preferentially utilize as substrates. Four different lipid products can
be generated by the different PI 3-K members: the singly phosphorylated
form PtdIns-3-P; the doubly phosphorylated forms
PtdIns-3,4-P2 and PtdIns-3,5-P2; and finally
the triply phosphorylated form PtdIns-3,4,5-P3 (Fig. 1).
INTRODUCTION
TOP
INTRODUCTION
PtdIns-3-P
PI-3,4-P2
PI-3,5-P2
PI-3,4,5-P3
PI 3-K as a ...
Concluding Remarks
REFERENCES
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Fig. 1.
The pathways for PI synthesis. The
white boxes indicate the PI 3-K lipid products.
The classes of PI 3-K enzymes that catalyze the phosphorylation of the
different PI 3-K substrates are indicated on top of the
horizontal arrows. Class I enzymes include Class
IA and IB. Kin, kinases;
Pase, phosphatases.
PI 3-K was first described as a PI kinase activity associated with the viral oncoproteins, v-Src, v-Ros, and polyomavirus middle T. Mutational studies of these oncoproteins more than 10 years ago indicated a critical role for the associated PI kinase in cell transformation (reviewed by Ref. 2).
Recent advances in the field have been achieved by the development of
new techniques to probe for the direct targets of PI 3-K lipid
products. The chemical synthesis of short chain fatty acid versions of
these lipids (3-5) has been a crucial step in determining the
specificity of lipid-binding proteins. Additionally, new cloning
strategies have been developed to isolate new lipid-binding proteins
(6). Here we will review the most recent advances in our understanding
of the role of PI 3-K in cell function by dissecting the contribution
of each of its lipid products.
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PtdIns-3-P |
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Regulation-- PtdIns-3-P is constitutively present in both mammalian and yeast cells (7, 8). It can be produced in vitro via phosphorylation of PtdIns by Class I, II, or III PI 3-Ks (Fig. 1). However, the majority of PtdIns-3-P in mammalian cells is probably produced by Class III PI 3-K (9). The mammalian Class III enzyme is highly related to the yeast Vps34 gene product (10) and, like the yeast enzyme, is specific for PtdIns and will not phosphorylate PtdIns-4-P or PtdIns-4,5-P2 (11).
Targets-- PtdIns-3-P was recently shown to specifically interact with a 70-residue protein module called the FYVE finger domain. This domain is a special type of RING zinc finger that is characterized by two zinc-binding sites and a highly conserved stretch of basic residues surrounding the third zinc-coordinating cysteine. Liposomes containing PtdIns-3-P were shown to associate with several FYVE domains (15-17). Other phosphoinositides bound poorly to the FYVE domains investigated, showing that this interaction is specific for PtdIns-3-P. Proper folding of the domain is important for its function because mutation in one of the zinc-coordinating cysteines or removal of zinc with EDTA or TPEN reduced PtdIns-3-P binding (16, 17). Moreover, mutations in the basic motif also eliminated binding (16). The interaction between FYVE domains and PtdIns-3-P is presumed to occur in vivo, because localization of the FYVE-containing protein EEA1 on early endosomes depends on an intact FYVE domain (17, 18) and on PI 3-K activity (based on wortmannin effects in mammalian cells) (19). When overexpressed in cells, the FYVE domain of EEA1 is sufficient to determine subcellular localization (16). Simonsen and colleagues (20) have shown that, in addition to PtdIns-3-P, the EEA1 protein associates with GTP-bound Rab5 through separate domains, and interactions with both PtdIns-3-P and GTP-Rab5 are necessary for the stable association of EEA1 with membranes in vivo.
Cellular Functions-- Mutations in the yeast Class III PI 3-K, VPS34, cause missorting of vacuolar proteins, changes in vacuole morphology, and defects in the endocytic pathway (reviewed in Ref. 10). In mammalian cells, inhibition of PI 3-K by the drug wortmannin blocks transport of proteins from the Golgi to the lysosome, inhibits early endosome trafficking, and causes the accumulation of prelysosomal vesicles (22, 23). Mutations in the PDGF receptor that disrupt its association with Class I PI 3-Ks interfere with trafficking of this receptor to the lysosome and its subsequent degradation (12).
With the identification of the FYVE-containing proteins as potential
targets for PtdIns-3-P, the mechanism by which this lipid is involved
in vesicle trafficking is now becoming clear. As discussed above,
PtdIns-3-P is necessary for the subcellular localization of EEA1, a
protein that regulates fusion of endocytic membranes (20, 24). The
mammalian FYVE-containing protein Hrs-2 and the yeast proteins Fab1p,
Vps27p, and Vac1p are involved in different vesicle trafficking events,
such as secretion and vacuole targeting (reviewed by Ref. 14).
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PI-3,4-P2 |
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Regulation-- PtdIns-3,4-P2 levels can be regulated by extracellular signals. PDGF stimulation of quiescent fibroblasts as well as fMLP peptide stimulation of neutrophils result in rapid PtdIns-3,4-P2 synthesis (7, 13, 25). Stephens and collaborators (25) have proposed that the elevation in PtdIns-3,4-P2 levels in these cells is caused by the dephosphorylation of PtdIns-3,4,5-P3 as opposed to the phosphorylation of PtdIns-4-P or PtdIns-3-P.
Recent studies have indicated that, in platelets,
PtdIns-3,4-P2 can also be synthesized by phosphorylation of
the 4-position of PtdIns-3-P by an unidentified PtdIns-3-P 4-kinase
(26, 27). Although the PtdIns-5-P 4-kinase (also called Type II
PtdIns-P kinase) can catalyze this reaction in vitro, it is
unlikely that this enzyme is responsible for the elevation of
PtdIns-3,4-P2 levels in vivo because PtdIns-3-P
is a poor substrate for this enzyme when compared with PtdIns-5-P
(28).
The class II PI 3-Ks can phosphorylate PtdIns-4-P to generate PtdIns-3,4-P2, independent of PtdIns-3,4,5-P3 synthesis (Fig. 1). The contribution of this pathway to the intracellular levels of PtdIns-3,4-P2 is unknown.
In summary, it is clear that mammalian cells have evolved a variety of mechanisms for independently controlling the levels of PtdIns-3,4-P2 and PtdIns-3,4,5-P3.
Targets--
The serine/threonine protein kinase B (PKB), also
known as Akt, is the most well characterized target of
PtdIns-3,4-P2. The PH domain of Akt has been shown to bind
phosphoinositides in vitro with the order of preference
being PtdIns-3,4-P2 > PtdIns-3,4,5-P3
PtdIns-4,5-P2 (30, 31). PtdIns-3,4-P2 binding
to Akt causes a 3-5-fold stimulation of its activity in
vitro (30-32). In thrombin-stimulated platelets, Akt activation
correlates with PtdIns-3,4-P2 production rather than
PtdIns-3,4,5-P3 production (30). Consistent with this,
integrin cross-linking causes PtdIns-3,4-P2 production
without PtdIns-3,4,5-P3 production and results in Akt
activation (27). In vivo, full activation of Akt also
depends on the phosphorylation of a threonine (Thr-308) and a serine
(Ser-473) (33). Phosphorylation of these residues was shown to be
dependent on PI 3-K. The Thr-308 kinase PDK1 (for
phosphoinositide-dependent kinase; also called PKB kinase) was
recently purified and cloned based on its ability to catalyze the
phosphorylation of Thr-308 of Akt in a
PtdIns-3,4,5-P3-dependent manner (34-37). Like
Akt, PDK1 contains a PH domain and binds with high affinity to
PtdIns-3,4-P2 and PtdIns-3,4,5-P3 (37). To understand the mechanism by which these lipids activate Akt in vivo, a model was proposed in which the PI 3-K lipid products are
involved in recruiting Akt and its upstream kinases to the membrane and
also in promoting conformational changes in Akt that expose Thr-308 and
Ser-473 to be phosphorylated by PDK1 and other kinases (reviewed in
Refs. 29 and 38).
PDK1 can also phosphorylate the activation loop of p70S6-K (36, 39) and PKC family members (40, 41) in vitro. In most cases, phosphorylation at the activation loop of these various kinases is necessary for activation, but phosphorylation of other residues is also required for full activity.
PKC expressed in baculovirus and PKC
purified from brain are
significantly activated by PtdIns-3,4-P2 and
PtdIns-3,4,5-P3 (42, 43). It is likely that the activity of
these isoforms is affected by PDK1 phosphorylation (
and
) as
well as by a direct interaction with these phosphoinositides (
).
Consistent with these in vitro studies, inhibition of PI 3-K
blocks PDGF and insulin-dependent activation of
p70S6-K in vivo (44),
insulin-dependent activation of PKC in vivo (45, 46), and PDGF-dependent membrane recruitment and
activation of PKC
in vivo (47). However, the enzymatic
activity of PDK1 is not dependent on phosphoinositides (48). Thus, the
requirement of PI 3-K for PDK1-dependent phosphorylation of
various enzymes probably reflects a role for PtdIns-3,4-P2
and PtdIns-3,4,5-P3 in co-localizing PDK1 and its
substrates at specific membranes.
Cellular Functions--
Activation of Akt mediates the
transduction of cell survival signals. Activated Akt can phosphorylate
and inactivate Bad, a protein involved in promoting cell death
(reviewed by Ref. 50). In addition to Bad, Akt must have other targets
that mediate cell survival because it promotes survival of cells that
lack Bad (49). Glycogen synthase kinase 3 and phosphofructokinase are
also in vitro substrates for Akt, implicating PI 3-K lipid
products in gluconeogenesis and glycolysis (51, 52).
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PI-3,5-P2 |
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Regulation--
In mouse fibroblasts, the major route for
PtdIns-3,5-P2 synthesis is wortmannin-sensitive and
involves the consecutive phosphorylation of PtdIns by a PI 3-K
(presumably the Class III enzyme) and of PtdIns-3-P by a PtdIns-3-P
5-kinase (53). In vitro, this second reaction can be
catalyzed by the PtdIns-P 5-kinases and
(also known as type I
PtdIns-P kinases) (54). Likewise, PtdIns-3,5-P2 synthesis
in yeast involves phosphorylation of PtdIns-3-P by a 5-kinase and
requires Vps34p PI 3-K (55). Fab1, a gene that is highly
homologous to the mammalian PtdIns-P 5-kinases, was recently identified
as the yeast PtdIns-3-P 5-kinase (56). Dramatic increases in
PtdIns-3,5-P2 levels were observed in response to hyperosmotic shock of yeast cells. In mammalian cells, the levels of
PtdIns-3,5-P2 decrease moderately with hyperosmotic shock
and increase with hypo-osmotic shock. In vitro,
PtdIns-3,5-P2 can also be generated through phosphorylation
of the novel lipid PtdIns-5-P by the Class IA PI 3-K
(28).
Targets-- PtdIns-3,5-P2 is a newly identified molecule, and no direct target for this lipid has been found. PH domain-containing proteins are likely candidates for PtdIns-3,5-P2 downstream effectors. Previous studies of lipid binding specificity of PH domains did not investigate this lipid.
Cellular Functions--
Because mutations in the yeast
Fab1 cause enlargement of the vacuole (57),
PtdIns-3,5-P2 may be involved in vesicle trafficking (reviewed by Emr and colleagues (94)).
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PI-3,4,5-P3 |
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Regulation--
The majority of the PtdIns-3,4,5-P3
synthesized in response to extracellular signals is, most likely,
generated by phosphorylation of PtdIns-4,5-P2 at the
3-position of the inositol ring (25). The Class I PI 3-Ks are the only
enzymes that can use PtdIns-4,5-P2 as a substrate to
synthesize PtdIns-3,4,5-P3 (Fig. 1). Activation of class
IA PI 3-Ks by growth factor stimulation of cells is mediated in
part by interaction of their SH2 domain with tyrosine-phosphorylated proteins and results in a rapid elevation of
PtdIns-3,4,5-P3 levels (reviewed by Ref. 2). Class
IA PI 3-Ks can also be regulated by the GTP-bound form of
the small G protein Ras (59). The Class IB PI 3-K can be
directly activated by the subunits of heterotrimeric G proteins
(reviewed in Ref. 58). In addition, one of the Class IA
enzymes (p110
) can be activated synergistically by phosphotyrosine peptides plus
subunits (60).
Recently, a PtdIns-4,5-P2-independent pathway for
PtdIns-3,4,5-P3 synthesis was described. PtdIns-P 5-kinases
and
have been shown to utilize PtdIns-3-P as a substrate to
produce PtdIns-3,4,5-P3 by phosphorylating the 4- and the
5-positions of the inositol ring in a concerted reaction (54, 61). The
contribution of this new pathway to intracellular levels of
PtdIns-3,4,5-P3 is still unknown.
Several PtdIns-3,4,5-P3 phosphatases have now been
isolated. Of special interest is the PTEN tumor suppressor protein (see below), which can dephosphorylate PtdIns-3,4,5-P3 at the
3-position (62), and SHIP (discussed above), which can dephosphorylate the 5-position (63). Little is known about the in vivo
metabolism of this lipid. However, it is resistant to hydrolysis by
phospholipase C, types ,
, and
(64).
Targets--
In addition to Akt, PDK1, and PKC (discussed
above), many targets for PtdIns-3,4,5-P3 have now been
described. Several of these proteins have PH domains that mediate
binding (for a review on PH domains see Ref. 65). Many
PtdIns-3,4,5-P3-binding PH domains can also bind to
PtdIns-4,5-P2, and only those that have at least a 10-fold
higher affinity for PtdIns-3,4,5-P3 than for PtdIns-4,5-P2 will be considered here.
The PH domain of the Bruton's tyrosine kinase (Btk) was shown to
interact with PtdIns-3,4,5-P3 and its head group, inositol 1,3,4,5-P4, with high affinity (66-68). Substituting
cysteine for arginine 28 (R28C) in the PH domain of Btk, a natural
mutation that causes X-linked immunodeficiency in mice, significantly
affects the binding of PtdIns-3,4,5-P3 and inositol
1,3,4,5-P4. In vivo, overexpression of the Class
IA PI 3-K enzyme p110* (a constitutively active form of PI
3-K) or Class IB PI 3-K was shown to enhance Btk
autophosphorylation and Src family kinase-mediated tyrosine phosphorylation of Btk (69, 70). This effect was inhibitable by
wortmannin and required the PH domain of Btk (69, 70). Phosphorylation
of Btk leads to its activation, as measured by its ability to regulate
tyrosine phosphorylation of PLC
2. Overexpression of Btk and PI 3-K
enhanced production of inositol 1,4,5-P3 in response to
cross-linking of surface immunoglobulin in B cells. Engagement of SHIP
to the inhibitory receptor Fc
RIIB1 blocks B cell receptor-induced
PtdIns-3,4,5-P3 elevation and Btk activation. Altogether,
these results indicate that PtdIns-3,4,5-P3, but not PtdIns-3,4-P2, is involved in activation of Btk by Src
family kinases through a mechanism that resembles activation of Akt by PDK1.
The protein Grp1 (general receptor for phosphoinositides) was cloned based on its ability to bind PtdIns-3,4,5-P3 in vitro (6). Analysis of its amino acid sequence revealed a PH domain and a Sec7 homology domain. The Grp1 PH domain is very selective for PtdIns-3,4,5-P3 compared with other phosphoinositides (73). The Sec7 homology domain of Grp1 was shown to function as a guanine nucleotide exchange factor for the small G proteins Arf1 and Arf5. Grp1 exchange activity toward myristoylated Arf1 can be enhanced in vitro by PtdIns-3,4,5-P3-containing micelles, suggesting that PtdIns-3,4,5-P3 regulates Grp1 by recruiting it to membranes where Arf is localized (73).
The presence of PH domains in a wide range of guanine nucleotide exchange factors for small G proteins (74) suggests that phosphoinositide regulation of these proteins may be widespread. PDGF-induced binding of GTP to the small G protein Rac depends on PI 3-K activation (75). This result suggests that PI 3-K lipids may directly affect the exchange factors for Rac. Indeed, PtdIns-3,4,5-P3 and PtdIns-3,4-P2 were shown to bind to the nucleotide exchange factor Vav and stimulate its exchange activity toward Rac, Cdc42, and RhoA (76). Interestingly, PtdIns-4,5-P2 was also able to bind to Vav, but in this case, the exchange activity of Vav was inhibited by this lipid. Because water-soluble (short chain fatty acid) lipids were used in these experiments, it was suggested that PtdIns-3,4,5-P3 binds to the PH domain of Vav and allosterically activates it.
The SH2 domains of Src and p85 (the PI 3-K Class IA
regulatory subunit) can bind PtdIns-3,4,5-P3 in competition
with phosphotyrosine-containing proteins (72). More recently,
PtdIns-3,4,5-P3 was shown to bind to the SH2 domains of
PLC and to enhance its phospholipase activity toward
PtdIns-4,5-P2 in vitro (77, 78). Inhibition of
PI 3-K activity (by wortmannin treatment, mutation of PI 3-K-binding sites in the PDGF receptor, or overexpression of dominant-negative enzyme) partially inhibits PDGF-dependent
inositol-1,4,5-P3 production in intact cells, implicating
PtdIns-3,4,5-P3 as a positive regulator of PLC
in
vivo. Another report showed that the PLC
PH domain also binds
PtdIns-3,4,5-P3 and mediates PLC
translocation to the
cell membrane in response to growth factors (79).
Cellular Functions--
With the identification of several
PtdIns-3,4,5-P3 targets, many of the cellular functions
attributed to PI 3-Ks can now be understood at the molecular level.
Elevation in cytosolic calcium in response to B cell stimulation
appears to be modulated by PI 3-K, based on studies with PI 3-K
inhibitors. This result can be explained by
PtdIns-3,4,5-P3-dependent activation of Btk and perhaps also by direct effects of PtdIns-3,4,5-P3 in
recruitment of PLC to the membrane (69, 70, 77, 79).
A role for PI 3-K in vesicle recruitment to the plasma membrane has been proposed based on the observation that wortmannin and dominant-negative PI 3-K block GLUT 4 translocation to the plasma membrane in response to insulin (80, 81). The observation that PtdIns-3,4,5-P3 mediates recruitment of Grp1 to membranes and enhances Grp1 nucleotide exchange activity toward Arf1 provides an explanation for how PtdIns-3,4,5-P3 may regulate coating and budding of intracellular vesicles (6, 73). As discussed above, a role for PtdIns-3-P and FYVE domain proteins in vesicle fusion is also likely.
PI 3-K recruitment and activation is also necessary for PDGF-induced chemotaxis and membrane ruffling (82, 83). PtdIns-3,4,5-P3 activation of Vav2 (or other Rac exchange factors) (76) and consequently binding of Rac to GTP may explain the mechanism by which PI 3-K is involved in growth factor and Ras-stimulated cytoskeleton rearrangements that lead to cell migration.
Several studies support the idea that PI 3-K is necessary for growth
factor and oncogene-induced cell proliferation. Recently, a natural
oncogenic form of PI 3-K, v-p3k, was isolated from a chicken
retrovirus that causes hemangiosarcomas, ASV16 (84). Expression of
v-p3k protein as well as its cellular counterpart, the chicken p110
PI 3-K, causes elevation in PtdIns-3,4-P2 and PtdIns-3,4,5-P3 levels, activation of Akt, and
transformation of chicken embryo fibroblasts. Another oncogenic form of
PI 3-K that consists of a truncated version of p85 (p65) associated
with the p110 catalytic subunit has been isolated from transformed lymphoid cells (85). In cells expressing this constitutively active PI
3-K, Akt is also up-regulated. Strong evidence indicating that
PtdIns-3,4,5-P3 is involved in cell proliferation came with the recent finding that the tumor suppressor protein, PTEN, is a
3-phosphatase that dephosphorylates PtdIns-3,4,5-P3 (62). The PTEN gene is deleted or mutated in a wide variety of
human cancers, and it is capable of suppressing the growth of glioma cells (86-88).
The gene encoding the mouse PI-3K adapter subunit, p85, has now been
disrupted by two independent groups (89, 90). Defects in B cell
development and proliferation were observed in both studies. This
phenotype resembles the phenotype of Btk-deficient mice. These data
support the hypothesis that PtdIns-3,4,5-P3 activation of
Btk is likely to mediate B cell functions in animals (89, 90).
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PI 3-K as a Protein Kinase |
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PI 3-K is a dual specificity kinase that can phosphorylate serine
and threonine residues in addition to phosphoinositide lipids (91, 92).
p110 can phosphorylate itself, the associated p85 regulatory
subunit, and the insulin receptor substrate (IRS1) (reviewed in Ref.
58). Because phosphorylation of p85 by PI 3-K decreases the lipid
kinase activity of the complex, it was proposed that the protein kinase
intrinsic to PI 3-K has a regulatory function. The possibility that the
protein kinase activity of PI 3-K plays a role in signaling is
suggested by a recent study. Bondeva et al. (93) have now
demonstrated MAPK activation by a PI 3-K
hybrid protein that has
protein kinase activity but lacks lipid kinase activity. Moreover,
membrane-bound PI 3-K
was unable to stimulate MAPK activation,
indicating that the substrate for PI 3-K protein kinase is not at the
cell membrane. On the other hand, this enzyme failed to stimulate Akt
consistent with Akt activation being dependent on
PtdIns-3,4-P2 and/or PtdIns-3,4,5-P3 synthesis
(93). These results show that PI 3-K-mediated signaling involves
independent pathways that lead to MAPK activation or Akt activation.
Activation of the MAPK pathway may be an additional mechanism by which
PI 3-K mediates the transduction of proliferation signals.
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Concluding Remarks |
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Given that PI 3-K is involved in so
many different cellular responses to a variety of different signals and
that several different proteins are direct targets for 3-phosphorylated
phosphoinositides (Fig. 2), an important question is: how is
specificity in downstream signaling maintained?
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One level of specificity may be obtained by synthesis of different lipid products by different PI 3-K isoforms. A second level of specificity can be obtained by recruitment of PI 3-K to specific subcellular compartments and a consequent increase in local production of lipids where a specific target may be available (for example, EEA1 recruitment by PtdIns-3-P and Rab5). Finally, it is possible that the specificity of the response is determined by convergence of two parallel pathways triggered by a specific signal (for example, Btk activation by PtdIns-3,4,5-P3 and Lyn).
As other targets for PI 3-K lipids are unveiled, the job of untangling
the intricate network of PI 3-K signaling will continue.
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ACKNOWLEDGEMENTS |
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We thank Dr. Rachel Meyers and Dr. David Fruman for the critical review of this manuscript.
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FOOTNOTES |
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* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999. This is the first article of five in "A Thematic Series on Kinases and Phosphatases That Regulate Lipid Signaling." This research was suported by National Institutes of Health Grant GM41890.
To whom correspondence should be addressed. Tel.: 617-667-0947;
Fax: 617-667-0957; E-mail: cantley{at}helix.mgh.harvard.edu.
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ABBREVIATIONS |
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The abbreviations used are: PI 3-K, phosphoinositide 3-kinase; PtdIns, phosphatidylinositol; PDGF, platelet-derived growth factor; fMLP, formyl-methionyl-leucyl-phenylalanine; PH, pleckstrin homology; PLC, phospholipase C; PKC, protein kinase C; MAPK, mitogen-activated protein kinase.
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