1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
2 Departments of Neuroscience, Pharmacology and Molecular Science, and Psychiatry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
* Author for correspondence (e-mail: kye{at}emory.edu)
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Summary |
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Key words: PIKE, GTPase, PI 3-kinase, 4.1N, PLC-1, GEF, ArfGAP
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Introduction |
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Identification of PIKE-S |
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The interaction between PIKE-S GTPase and PI 3-kinase is GTP dependent, like that between Ras and PI 3-kinase (Rodriguez-Viciana et al., 1994; Ye et al., 2000
). Cytoplasmic PI 3-kinase activators, such as receptor tyrosine kinases (RTKs) and Ras, bind to one of the two PI 3-kinase subunits, but PIKE-S directly associates with both p85 and p110 (Ye et al., 2000
). The interaction between PIKE-S and p85 is dependent on the N-terminal 23 residues, to which protein 4.1N also binds, but this region is not necessary for p110 to bind to PIKE-S. Thus, 4.1N competes with PI 3-kinase for binding to PIKE-S. Co-transfection of 4.1N into cells with wild-type PIKE-S abolishes the PIKE-S-induced activation of PI 3-kinase activity. This loss of activation is associated with the failure of PIKE-S to co-precipitate with PI 3-kinase in cells that have been co-transfected with 4.1N.
In addition to binding protein 4.1N and PI 3-kinase, PIKES also robustly associates with PLC-1. The third proline-rich domain of PIKE-S binds directly to the Src-homology 3 (SH3) domain of PLC-
1 (Ye et al., 2002
), which is a physiological GEF for PIKE-S. This GEF activity is mediated by the SH3 domain of PLC-
1; its phospholipase catalytic activity is not required. The SH3 domain but not the phospholipase catalytic activity of PLC-
1 is necessary for its mitogenic actions, which probably involve activation of nuclear PI 3-kinase (Ye et al., 2002
). The finding that the PLC-
1 SH3 domain is a physiological GEF for PIKE-S indicates that this domain can display biological activity, which might account for its mitogenic activity. This system responds to signaling from the plasma membrane, since NGF triggers nuclear translocation of PLC-
and its binding to PIKE-S. These findings are consistent with numerous reports of nuclear roles for PLC-
(Bertagnolo et al., 1998
; Bertagnolo et al., 1995
; Diakonova et al., 1997
; Marmiroli et al., 1994
; Martelli et al., 1994
; Neri et al., 1998
; Zini et al., 1995
).
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PIKE-S in nuclear PI 3-kinase regulation |
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PI 3-kinase is a key regulator of many cellular processes, including cell proliferation, survival, motility, vesicular trafficking and carbohydrate metabolism. It is activated by both RTKs and membrane-associated GTPases. Activated PI 3-kinase generates critical second messengers: the D3-position-phosphorylated phosphoinositides, which bind to the PH domains of numerous signaling molecules, including 3-phosphoinositide-dependent protein kinase 1 (PDK1), Akt/PKB, SGK and PLC-1. Although much has been learned about PI 3-kinase signal transduction in the cytoplasm, almost nothing is known about the role of this enzyme in the nucleus, despite previous studies showing that it is present there (Bacqueville et al., 2001
; Bavelloni et al., 1999
; Kim, 1998
; Lu et al., 1998
; Neri et al., 1994
; Tanaka et al., 1999
; Ye et al., 2000
). Cytoplasmic PI 3-kinase activation requires activated RTKs [e.g. platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), CD28, etc.] or GTPase proteins such as Ras. However, none of these known PI 3-kinase activators is present in the nucleus. Stimulation of cells with NGF nevertheless activates nuclear PI 3-kinase and consequently leads to nuclear accumulation of 3-phosphorylated phosphoinositide lipids (Neri et al., 1999
; Tanaka et al., 1999
). PI 3-kinase translocates to the nucleus following NGF treatment with a time course that resembles the activation of PIKE-S (Ye et al., 2000
). NGF also elicits nuclear translocation of 4.1N over a period of an hour; 4.1N thus lags behind PI 3-kinase and the peak activation of PIKE-S elicited by NGF. The decline of activated nuclear PI 3-kinase, which coincides with the appearance of nuclear 4.1N, might involve 4.1N sequestering nuclear PIKE-S away from PI 3-kinase. The decline in NGF-induced stimulation of PIKE-S GTPase activity takes place at about the same time and so might also contribute to the decline in nuclear PI 3-kinase activity.
Nuclear PI 3-kinase localizes to both the nuclear envelope and the internal nuclear matrix, which fits with the localization of its substrate PtdIns(4,5)P2. The tumor suppressor PTEN, a phosphatidylinositol phosphatase specific for the 3-position of the ring that inhibits PI 3-kinase)/Akt signaling (Yamada and Araki, 2001) also occurs in the nucleus.
Targets of cytoplasmic PI 3-kinase have been studied extensively. The lipid products of PI 3-kinase in the cytoplasm activate a variety of kinases, including Akt and PDK1 (Alessi et al., 1997; Frech et al., 1997
). These activities influence cytoskeletal rearrangements, vesicle transport and apoptosis, which are largely cytoplasmic events. Some cytoplasmic targets of PI 3-kinase, such as Akt, translocate to the nucleus, but whether they function as downstream targets of PI 3-kinase in the nucleus is unknown. Thus, the nuclear processes regulated by the PI 3-kinase signaling system have not yet been established. Note that nuclear phosphatidylinositol (3,4,5)trisphosphate [PtdIns(3,4,5)P3] facilitates nuclear translocation of proteins with a PtdIns(3,4,5)P3-binding motif (the PH domain). Both nuclear PI 3-kinase and PtdIns(3,4,5)P3 are necessary for the nuclear translocation of PKC-
(Neri et al., 1999
). Furthermore, a PtdIns(3,4,5)P3-binding protein, PIP3BP, is exported out of the nucleus by constitutively activated PI 3-kinase (Tanaka et al., 1999
). The interaction of the PH domain and PtdIns(3,4,5)P3 is responsible for the relocation of PIP3BP. These results suggest that PIP3BP can shuttle between the nucleus and the cytoplasm, and this is dependent on the activity of PI 3-kinase, indicating that there may be an unknown function of PI 3-kinase in the nucleus.
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A nuclear PLC-![]() |
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The mitogenic activity of PLC-1 is not dependent on its phospholipase activity, but requires its SH3 domain (Huang et al., 1995
; Smith et al., 1994
; Ye et al., 2002
). Several studies have suggested cross-talk between PLC-
1 and PI 3-kinase in the cytoplasm. For example, the PtdIns(3,4,5)P3 generated by PI 3-kinase influences PLC-
1 membrane translocation and activation by binding to its PH domain and a C-terminal SH2 domain (Bae et al., 1998
; Carpenter and Ji, 1999
), and activation of PLC downregulates PI 3-kinase by at least two mechanisms: (1) inhibition of insulin receptor substrate (IRS)-1-associated PI 3-kinase; and (2) acute activation of a PtdIns(3,4,5)P3 5-phosphatase. To what extent might PLC-
1 and PI 3-kinase engage in intranuclear cross-talk? These two enzymes use the same substrate, PtdIns(4,5)P2; their reciprocal activation might thus influence the availability of PtdIns(4,5)P2 for various signaling pathways (Batty et al., 1997
). In addition, as described above, PLC-
1 functions as a GEF for PIKE-S and thereby activates PI 3-kinase. Nuclear phosphoinositide signaling, exemplified by PLC-
1-PI 3-kinase cross-talk, might regulate cell-cycle progression and differentiation independently of cell-surface phosphoinositides (Fig. 2) (Maraldi et al., 1999
; Payrastre et al., 1992
).
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Proteins 4.1 and PIKE-S |
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Protein 4.1 occurs in both presynaptic sites and postsynaptic densities (Biederer and Sudhof, 2001; Ohara et al., 1999
; Scott et al., 2001
; Shen et al., 2000
; Walensky et al., 1999
). Immunohistochemical studies reveal several patterns of neuronal staining, with localization in neuronal cell bodies, dendrites and axons. In certain neuronal locations, including the granule cell layers of the cerebellum and dentate gyrus, a distinct punctate-staining pattern is observed, which is consistent with synaptic localization. In primary hippocampal cultures, mouse 4.1N is enriched at discrete sites of synaptic contact, colocalizing with the postsynaptic density protein of 95 kDa (PSD-95; a postsynaptic marker) and glutamate receptor type 1 (GluR1), a member of the AMPA family of ionotropic, excitatory postsynaptic glutamate receptors (Walensky et al., 1999
). CASK, a member of the MAGUK family involved in the organization of membrane-associated protein complexes, localizes at both the presynaptic and postsynaptic excitatory synapses (Hsueh and Sheng, 1999
), where it binds to a neuronal cell-surface protein, neurexin, through its PDZ domain and HOOK region for protein 4.1N (Biederer and Sudhof, 2001
). 4.1N also binds to the membrane-proximal region of GluR1 in vivo and is implicated in AMPA receptor clustering and association with the actin cytoskeleton (Shen et al., 2000
).
The 4.1 protein family members contain, in addition to FERM and spectrin/actin-binding domains, CTDs that bind to several other proteins. These include nuclear mitotic apparatus protein (NuMA) (Mattagajasingh et al., 1999; Ye et al., 1999
), the AMPA receptor GluR1 (Shen et al., 2000
) and PIKE-S (Ye et al., 2000
). Although 4.1N binds to PIKE-S, it does not affect its GTPase activity and presumably acts as an anchoring protein. One possibility is that 4.1N links PIKE-S to the nuclear matrix. This idea is consistent with the finding that PI 3-kinase is also detected tightly bound to nuclear matrices of HL-60 cells isolated by nuclease treatment and high salt extraction. Four days of ATRA (all-trans retinoic acid) treatment induces a striking increase in the level of nuclear-matrix-bound PI 3-kinase (Marchisio et al., 1998
). Alternatively, 4.1N could link PIKE to postsynaptic receptors such as GluR1, which would indicate that it also functions at synapses (Fig. 3) (Shen et al., 2000
).
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PIKE-L binds Homer and mediates anti-apoptosis and stimulation of PI 3-kinase by metabotropic glutamate receptors |
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Sequence analysis led to the discovery that PIKE-L binds to the adaptor protein Homer 1c. Residues 187-190 of PIKE-L have the sequence PKPF, which fit the consensus motif (PxxF) present in proteins that bind to the EVH1 domain of Homer (Xiao et al., 2000). PIKE-L and Homer 1C coprecipitate robustly, and the interaction is dependent upon the portion of PIKE-L that contains the PKPF sequence. Mutation of P187 of PIKE-L abolishes binding of PIKE-L to Homer 1C and provides a useful tool to analyze the importance of this binding in various signaling cascades.
What signaling cascades are associated with Homer proteins? This family of adaptor proteins is localized to postsynaptic densities, serving to crosslink cytoplasmic regions of group I metabotropic glutamate receptors (mGluRs) with Ins(1,4,5)P3 receptors as well as SHANK proteins (Xiao et al., 2000). The mGluRs comprise three groups. Group I receptors (mGluR1 and mGluR5) stimulate PLC-ß through G proteins, leading to the formation of Ins(1,4,5)P3 and associated calcium mobilization. By contrast, group II and group III receptors are negatively coupled to adenylyl cyclase (De Blasi et al., 2001
). One particularly prominent action of group I mGluRs is to protect neurons from apoptotic death (Copani et al., 1995
). Binding of mGluRI to Homer and thereby PIKE-L occurs only in the case of the group I class of mGluRs, which are the only forms that contain the Homer-ligand PxxF motif.
The association of mGluR1 with PIKE-L via Homer 1C suggests that mGluR1 might activate PI 3-kinase separately from its well-known activation of PLC. This pathway has been verified by the demonstration that transfection of HEK293 cells with mGluR5 stimulates PI 3-kinase activity but mutants of mGluR5 that do not bind Homer fail to activate PI 3-kinase (Rong et al., 2003). Moreover, Homer mutants that do not bind GluR5 block PI 3-kinase activation. In hippocampal cultures, mGluR activation increases PI 3-kinase activity, whereas infection with an adenovirus containing a dominant-negative form of PIKE-L blocks such activation. In hippocampal cultures, delivery of the Homer-binding motif of PIKE as a dominant-negative construct blocks mGluR stimulation of PI 3-kinase (mutant peptides that do not bind Homer have no effect). Finally, mGluR activation fails to stimulate PI 3-kinase in the cerebellum, a brain region that is devoid of PIKE-L.
A major action of group I mGluRs is prevention of apoptosis, and this appears to be mediated by PIKE-L and PI 3-kinase (Rong et al., 2003). In hippocampal cultures, mGluR activation and PIKE-L transfection block the apoptotic effects of staurosporine and other agents. By contrast, a PIKE-L dominant-negative construct augments apoptosis, and a PIKE construct that cannot bind Homer prevents the anti-apoptotic actions of mGluR activation. Additionally, mGluR activation does not block apoptosis in the cerebellum, which lacks PIKE-L.
PIKE-L may have other activities besides mediating the effects of mGluR on PI 3-kinase and apoptosis (Fig. 4). Some possibilities are suggested by the structure of PIKE-L. Its C-terminal region contains an ArfGAP domain and two ankyrin repeats. GTPases are typically activated by GAP proteins, but PIKE-L appears to be the first GTPase that contains a GAP sequence within its own structure. Whether the ArfGAP domain functions as an internal GAP for the GTPase activity of PIKE-L remains to be determined, although there are instances of ArfGAP domains exerting such activity (Xia et al., 2003). An alternatively spliced form of PIKE-L that lacks the N-terminal domain and its three proline-rich areas has been identified as centaurin-
(Xia et al., 2003
).
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Mediation of anti-apoptotic actions is the only mGluR function thus far examined in connection with PIKE. Group I mGluRs exert a variety of neuronal activities, influencing motor learning and coordination via cerebellar Purkinje cells (Aiba et al., 1994) and influencing long-term potentiation in the hippocampus (Lu et al., 1997
). Conceivably, PIKE-L also participates in these activities.
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Concluding remarks |
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PIKE-L may have even broader relevance, displaying a breadth of influences in mGluR signaling. Stimulation of mGluRI by agonists increases neuronal survival and prevents apoptosis. The recent work indicates that a complex containing mGluRI, Homer 1c, PIKE-L and PI 3-kinase is responsible for the anti-apoptotic effects of mGluRI activation. PIKE-L could also have additional functions beside its anti-apoptotic role. For example, it might regulate synaptic plasticity by coupling mGluRI to the AMAP receptor.
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Acknowledgments |
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