(The FASEB Journal. 2000;14:2618-2622.)
© 2000 FASEB
Patterns within protein/polyphosphoinositide interactions provide specific targets for therapeutic intervention1
CHRISTOPHER P. BERRIE2 and
MARCO FALASCA*
Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy; and
* Department of Oncology and Neuroscience, Section of Medical Oncology, University ‘G. D’Annunzio’ Medical School, 66100 Chieti, Italy
2Correspondence: Department of Cell Biology and Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Consorzio Mario Negri Sud, Via Nazionale, 66030 Santa Maria Imbaro (Chieti), Italy. E-mail: berrie{at}cmns.mnegri.it
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ABSTRACT
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Signaling pathways involving the inositol polyphosphates and the
polyphosphoinositides have become intricately linked with a number of
disease states. More recently, this has principally involved the
3-phosphorylated products of phosphoinositide 3-kinase, an enzyme that
itself shows oncogenic activity and has hence become of interest in the
design of antitumorigenic drugs. The downstream effectors of
phosphoinositide 3-kinase are involved in different aspects of cellular
signaling and cytoskeleton and trafficking events that are linked to
specific polyphosphoinositide binding properties of specific protein
domains, which themselves have emerging roles in specific disease
states. Our recent findings have demonstrated that there is a
selectivity of the intracellular effects of extracellularly applied
inositol polyphosphates in their abilities to inhibit a range of
growth-related in vivo assay conditions, and that these
can themselves be linked to the inhibition of the membrane localization
of a green fluorescent protein (GFP) -tagged PH domain. We propose that
GFP fusions of the polyphosphoinositides binding domains of specific
proteins of interest can be used in high-throughput investigations of
the therapeutic value of specific inositol polyphosphates analogs.
Inhibition of in vivo membrane targeting of these
domains from proteins involved in cell growth and tumorigenesis can
thus be used in the search for new anticancer drugs.—Berrie, C. P., Falasca, M. Patterns within protein/polyphosphoinositide
interactions provide specific targets for therapeutic intervention.
Key Words: phosphoinositide 3-kinase • polyphosphoinositides • inositol polyphosphates • PH/FYVE/HIKE domains • cancer therapy
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INOSITOL POLYPHOSPHATES LEVELS AS THERAPEUTIC TARGETS
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IT IS STILL just over 30 years since the higher
inositol polyphosphates (IPPs)—namely, inositol (1, 3, 4, 5,
6)-pentakisphosphate (Ins13456P5) and
inositol hexakisphosphate (InsP6;
phytic acid)—were first reported to be naturally occurring components
of mammalian cells. Since then, their extracellularly applied,
intracellular effects have been noted (1)
; furthermore,
early InsP6 investigations
demonstrated in vivo effects in diverse cell systems,
including the enhancement of Ca2+ influx and
aspartate release in cultured cerebellar neurons (2)
, the
stimulation of Ca2+ uptake in cultured anterior
pituitary cells (3)
, the priming of the stimulated
respiratory burst in human neutrophils (4)
, and the
excitation of rat medullary sympathoexcitatory neurons in
vivo (5)
. Interest in the biological activities of
the IPPs has thus further increased (see refs 6
, 7
for
reviews), with particular emphasis on the potential anticancer actions
of InsP6 emerging more recently (see
ref 8
for review).
The use of lithium to potentially modulate cellular inositol and/or IPP
levels via its action as an inhibitor of the inositol monophosphatases
has been used both in the treatment of mood disorders and in numerous
experimental systems. However, lithium also induces a rapid increase in
phosphoinositide 3-kinase (PI3K) activity and Akt-1 phosphorylation in
cerebellar neurons, an effect that is blocked by PI3K inhibitors
(9)
. Furthermore, the identification of lithium regulation
of a human enzyme (10)
and a rat gene (11)
indicates that there indeed may be other targets in the mechanism of
action of lithium. As such, and in the light of the emerging in
vivo specificities of the inhibition of various signaling pathways
by specific IPPs (see below), the mechanisms of these diverse in
vivo effects of lithium now need to be reconsidered.
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PtdIns 3-KINASE PRODUCTS, PH DOMAINS, AND MEMBRANE TARGETING
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Along with the well-known lipid-signaling pathway that
involves the 4- and 5-phosphorylation of phosphatidylinositol (PtdIns),
which results in the production of phosphatidylinositol (4,
5)-bisphosphate (PtdIns45P2) at the
plasma membrane, these lipids are also substrates for the newer family
of PI3Ks. There have been three main classes of the PI3Ks described
according to their in vitro lipid substrate specificities,
structures, and regulation: Class I, which 3-phosphorylates PtdIns,
PtdIns 4-phosphate (PtdIns4P), and
PtdIns45P2, and possesses both
catalytic (e.g., p110
, ß, 
) and regulatory (e.g., p85, ß)
subunits; Class II, which 3-phosphorylates PtdIns and
PtdIns4P selectively (e.g., PI3K-C2, ß); and Class III,
which 3-phosphorylates PtdIns selectively and is represented by the
yeast Vps34p catalytic and the Vps15p regulatory subunits (see ref
12
for review). A Class IV of nonconventional PI3Ks has
also been suggested (13)
. There are thus four different
potential lipid products from the 3-phosphorylation of the
phosphoinositides: PtdIns 3-phosphate (PtdIns3P), PtdIns (3,
4)-bisphosphate, PtdIns (3, 5)-bisphosphate, and PtdIns (3, 4,
5)-trisphosphate (PtdIns345P3). Each
of these PPIs appears to have its own specific targets and functions in
the cell (see ref 14
for review), and include the
mediation of signal transduction, cytoskeleton rearrangements and/or
membrane trafficking, modulating these systems via specific
interactions with certain emerging families of lipid
recognition/binding domains (see refs 6
, 7
, 14
, 15
for
reviews), of which the pleckstrin homology (PH) domain is now the
largest represented. The PH domain is a well-recognized,
multifunctional structural domain consisting of some 100 to 120 amino
acids that share a specific tertiary structure (see refs 16
, 17
for recent reviews). Within a year of its initial definition,
reports of the 3-dimensional structure appeared and the list of
proteins containing PH domains began; a few hundred eukaryotic proteins
with a variety of functions are now listed as containing PH domains
(see ref 18
for further details). The common theme is that
the PH domain itself has no catalytic properties and that its presence
is generally associated with proteins that need to be positioned at or
near membranes; this has led to the proposal that they are involved in
the tethering of proteins to specific membranes, where the proteins are
required for their function (19
, 20)
.
In this context, whereby many diverse proteins can be activated
via their recognition of and binding to specific membrane PPIs, and
more particularly with respect to the generation of specific
3-phosphorylated PPIs that have now been implicated in the regulation
of numerous cellular processes, such as growth, proliferation,
survival, differentiation, and cytoskeleton rearrangements
(20)
, a new field for drug design has opened. Thus, the
ability to control the activities and specificities of the PI3Ks and
their lipid products allows for the potential of interfering in any of
these PI3K/PPI binding domain-mediated cellular processes. Furthermore,
with the more recent reports indicating that the candidate tumor
suppressor PTEN is not just a dual specificity protein phosphatase, but
also a phosphoinositides 3-phosphatase (21)
, its
involvement in these PI3K/PH domain-mediated cellular processes can
also be targeted for drug design. However, whereas these approaches can
allow for specificity at the level of the selection between pathways
that do and do not involve the activation of PI3Ks (see, for instance,
our recent report; ref 22
), it is also clear that with the
wide ranging effects of the PI3K-mediated cellular interactions, there
is the need for a high level of inbuilt specificity in any drug design
approach.
Therefore, PI3K is an attractive therapeutic target, and specific
inhibitors of the kinase should prove useful in cancer therapy,
particularly the oncogenic potential of PI3K. Our attention, however,
is focused on the mechanisms of membrane targeting mediated by the
lipid products of PI3K. Ligands of the main protein targets of these
lipids, and more specifically the PH domain, have the potential to
antagonize the activation of specific proteins by inhibiting their
translocation to the plasma membrane (or to any specific membrane
compartment). Indeed, as different PH domains possess different binding
affinities toward different IPPs, this increases the possibility of
specifically inhibiting a particular membrane-targeted protein. Hence,
this introduces a novel aspect of antagonism of PI3K signaling pathways
that could give us the potential to block a very specific downstream
target without interfering with all the other PI3K-mediated signals. In
combination with our recent work (22)
and some slowly
emerging (and often unexpected) patterns (see also below), we propose
here that in the same way that each specific phosphate group around the
head group of each specific PPI can promote unique functional roles in
cells, the IPPs, the water-soluble head groups of these PPIs, can
provide specific antagonists of these functions. Hence, it is possible
to design specific drug structures in order to mimic, and thus inhibit,
known protein structure recognition specificities.
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FURTHER PROTEIN DOMAIN/POLYPHOSPHOINOSITIDE RECOGNITION PATTERNS
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Although the PH domain as a structural protein motif is the most
well defined, the first specific IPP/PPI binding motifs that were
described were the short (10 to 20 amino acids) lysine/arginine-rich
sequences that are present in a number of cytoskeleton proteins and in
the C2 domains of particular proteins, such as the C2B domain of
synaptotagmin (see refs 7
, 23
for reviews). Although the
actual sequences and specificities appear not to have always been very
well defined, there may now be an emerging importance of these
interactions in the regulation of cytoskeleton-plasma membrane adhesion
by PtdIns45P2 (24)
. More
recently, and perhaps more important, after the initial report that
PtdIns3P is involved in intracellular traffic in yeast
(25)
and the definition of a common structural motif in
the membrane localization of specific proteins, the cysteine-rich,
‘zinc finger’ FYVE domain and its role in membrane trafficking events
in the secretory and endocytic pathways has become established (see
refs 26
27
28
for reviews).
At the same time, two additional sequences of 
20 amino
acids have been proposed. The first of these has been named the HIKE
motif, and was originally reported to be a candidate binding site for
specific PH domains (29)
; its ability to also bind to the
PPIs has been demonstrated in many cases because, as a motif, it
includes the lysine/arginine-rich sequence of gelsolin and is included
in the PH domain of Bruton’s tyrosine kinase (Btk). The importance of
mutations in HIKE regions of specific proteins has emphasized its
involvement in various disease states (see ref 30
for
review). The other new PPI binding region is present in the kinase
domain of the PtdIns phosphate kinases; it determines both the
enzymatic specificity and subcellular targeting of these kinases, and
hence controls their signal specificity and function (31)
.
The recent definition of a role for PtdIns4P 5-kinase as
a critical modulator of thrombin- and Rac-dependent actin assembly
indicates the emerging importance of these enzymes (32)
.
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PHYSIOLOGICAL TARGET SPECIFICITIES AND DISEASE
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With the rising importance of the PPIs in signal transduction,
cytoskeleton rearrangements, and membrane trafficking that began less
than 10 years ago, there has been an increase in the number of reports
of specific effects of these lipids in many diverse in vitro
systems. Based on these known domain recognition/mutation patterns and
with specific reference to known and emerging mutation/disease
patterns, we aim to discuss some of these effects, their relationships
to disease states and the specificities of protein/PPI interactions,
and the evidence that they do indeed have relevance in vivo.
Mutation causes disease
In this context, perhaps the most well-defined system with regard
to mutational analysis at the genetic level is the case of Btk. Btk
plays a critical role in B cell development and proliferation, and some
of the genetic mutations give direct links between PH domain
membrane-targeting and protein function; some 20% (ca. 25) of the
known genetic substitutions, insertions and/or deletions in the Btk
gene have already been attributed to altered PH domain function in
human X-linked agammaglobulinemia (XLA; 18
). One of the
most severe forms of XLA arises from a single amino acid substitution
(Thr33Pro) in that part of the PH domain that coincides with the HIKE
motif (18
, 30)
. Although numerous other genetic mutations
attributed to XLA also exist in the SH2, SH3, and kinase domains of Btk
(18)
, this is a direct example of how interference with
specific PH domain/membrane targeting can be used to inhibit the
‘normal’ activities of PH domain-containing proteins. As another
direct linkage, faciogenital dysplasia (FGD; Aarskog-Scott syndrome) is
a rare X-linked multisystemic disorder that leads to numerous physical
abnormalities arising primarily from an insertion mutation in the FGD1
gene, which results in a frameshift and a termination signal that
results in the loss of the carboxyl terminus half of the protein
(18)
. This mutation leads to the loss of the two PH
domains and the FYVE domain, with the remaining protein being
nonfunctional. Even though the significance of these three potential
lipid binding domains remains to be determined, this is an example
where a PH domain is implicated in protein–protein binding, as a
Cdc42-specific guanine-nucleotide exchange factor (33)
. In
the case of the actin regulatory protein gelsolin, a single amino acid
substitution in the HIKE motif has been described in a position just
before the second of its two earlier defined lysine/arginine-rich, PPI
binding regions (Asp187Asn and Asp187Tyr; 18
, 30
). These
mutations lead to the Finnish-type hereditary amyloidosis and
demonstrate the importance of the PPI binding domains and the membrane
localization of this protein in its actin-severing activity. These
examples of the importance of the PPI binding regions in the normal
function of specific proteins and the emerging oncogenic potential of a
number of proteins involved in such interactions lead us to the
specific inhibition of pro-oncogenic signals.
Oncogenic inhibition
The activation of Akt (RAC/protein kinase B) by the
PtdIns345P3-dependent protein kinase
(PDK1) regulates the downstream phosphorylation of further signaling
proteins, which in turn leads to the choice of cellular proliferation
or apoptosis (34
, 35)
. The ability to inhibit this
activity in vivo via our recent demonstration of the
disruption of its membrane localization by selective IPPs
(22)
represents an important control point in the
regulation of cell survival that can be exploited as an antitumor
target due to the pro-oncogenic activity of Akt. At the same time, many
studies of the phospholipase C (PLC) family of enzymes have
concentrated on the interactions of PLC
with
PtdIns45P2, whereby a bisubstrate
model of membrane localization by PH domain binding to
PtdIns45P2, followed by repeated
hydrolysis of further PtdIns45P2
molecules via the catalytic site, has been proposed (see ref
17
for review). However, with specific reference to tumor
cell invasiveness, a central role for PLC has been proposed; as
PLC signaling is promoted via a number of receptor-activation
pathways, such as the EGF receptor and the PDGF receptor, and since
these pathways also promote cell motility, the potential for PLC
inhibition as an antitumor target has emerged more recently
(36)
. Since this PLC activation is stimulated via
PI3K-induced, PH domain-mediated membrane targeting (37)
,
the ability to selectively inhibit this interaction via selective
effects of the IPPs becomes a target for inhibition of tumor cell
invasiveness.
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INOSITOL POLYPHOSPHATE INTERACTIONS IN VIVO
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Considering the IPPs themselves, early investigations into their
biological activities arose principally as a result of the known second
messenger actions and metabolic pathways of inositol (1, 4,
5)-trisphosphate, and the early observations of the suppression of cell
proliferation and tumor formation by
InsP6 (8)
. After this,
numerous in vitro systems were able to demonstrate that the
higher IPPs, particularly InsP5 and
InsP6, have various ‘binding
proteins’ in cells (see refs 6
, 7
for reviews). However,
the mechanism of the action of InsP6
remains to be satisfactorily explained (see ref 8
for
review and further comment). Specific intracellular roles have now been
proposed for extracellularly applied, cell permeant, hydrolyzable
esters of other specific higher IPPs: inhibition of
Ca2+-activated Cl-
channels by inositol (3, 4, 5, 6)-tetrakisphosphate (38)
,
with the intracellular levels of this
InsP4 being controlled by inositol (1,
3, 4)-trisphosphate inhibition of its 1-phosphorylation
(39)
, and inositol (1, 4, 5, 6)-tetrakisphosphate
inhibition of EGF-induced inhibition of
Ca2+-mediated chloride secretion in intestinal
epithelia (40)
. Furthermore, with the demonstrations that
InsP6 (see ref 8
) and
inositol (1, 3, 4, 5)-tetrakisphosphate
[Ins(1345)P4; 22
] can
rapidly enter cells, our recently reported selective inhibition of
PI3K-dependent cell growth by extracellularly applied Ins
(1345)P4 and Ins
(13456)P5 (22)
confirms
the potential for the use of these higher IPPs as anticancer drugs.
Whereas a role for the IPPs in the inhibition of PI3K-dependent
pathways has been suggested (14
, 22
, 40
, 41)
, with the
more recent evidence of their differing specificities for diverse
physiological targets (see above), and with the newly emerging
importance in disease of not just the PH domain, but also the FYVE
domain and the HIKE motif (see above), we propose that the selectivity
of these compounds is due to specific recognition sequences within
these domains. Hence, by following these selectivities from the
interactions of known IPPs/PPIs with specific protein domains/motifs, a
new area of design of anticancer drugs emerges for the future.
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CONCLUSIONS
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Through the gathering and expansion of information around these
protein/PPI interactions, we propose a unifying hypothesis that extends
beyond the IPPs and leads to modifications around the known active IPP
head groups. Thus, starting from an inositol head group with a known
activity toward a specifically defined target for therapeutic
intervention, the design of novel active compounds can begin with the
search for chemically modified derivatives that display higher
affinities and specificities toward this target protein. This approach
will provide a novel framework for the orientation of future
investigations that should result in the development of new active
molecules. How can we test this hypothesis? As with our recent study
(22), the use of GFP-fusion proteins to investigate the ability of IPP
analogs to interfere with the in vivo membrane targeting of
the selected therapeutic target provides a valuable tool in the study
of their in vivo efficacy and selectivity. This, combined
with biochemical studies of the protein activation and the
pharmacokinetic properties of the new IPP analogs, can lead to the
design of antitumorigenic drugs that act by mimicking known protein
structure specificities at the level of their membrane localization
through the protein/PPI interactions.
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ACKNOWLEDGMENTS
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We would like to thank Saverio Alberti (Consorzio Mario Megri Sud,
Italy) for a preview of work in press and both Saverio Alberti and
Roberto Buccione (Consorzio Mario Megri Sud, Italy) for critical
appraisal of the manuscript. The authors’ work has been supported by
the Italian Federation for Cancer Research (FIRC), the Italian National
Research Council (Convenzione CNR-Consorzio Mario Negri Sud), and
Telethon Italia (328/bi and E0841).
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FOOTNOTES
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1 NOMENCLATURE: The generic forms of IPPs and PPIs are used with respect to the inositol polyphosphates and polyphosphoinositides, whereas the unspecified isomers of the IPPs are
given without the phosphate position numbering [e.g., InsP3; except in the case of InsP6, which represents inositol (1,2,3,4,5,6)-hexakisphosphate, the only isomer of this IPP]; the indication of specific inositol (poly)phosphates and (poly)phosphoinositides are represented by the example of Ins145P3 and PtdIns45P2. PI3K is also used in the generic form to represent the family of phosphoinositide (PI) 3-kinases. 
Received for publication April 27, 2000.
Accepted for publication June 5, 2000.
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ABSTRACT
INOSITOL POLYPHOSPHATES LEVELS...
