The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function
Year: 1999
Type: review
Abstract: Phosphoinositide 3-kinases (PI 3-Ks) 1The 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. 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 (1Domin J. Waterfield M.D. FEBS Lett. 1997; 410: 91-95Crossref PubMed Scopus (209) Google Scholar), 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). 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. 2Cantley L.C. Auger K.R. Carpenter C. Duckworth B. Graziani A. Kapeller R. Soltoff S. Cell. 1991; 64: 281-302Abstract Full Text PDF PubMed Scopus (2186) Google Scholar). 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 (3Wang D.-S. Chen C.-S. Org. Chem. 1996; 61: 5905-5910Crossref Scopus (56) Google Scholar, 4Falck J.R. Abdali A. Bioorg. Med. Chem. Lett. 1993; 3: 717-720Crossref Scopus (15) Google Scholar, 5Prestwich G.D. Acc. Chem. Res. 1996; 29: 503-513Crossref Scopus (107) Google Scholar) 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 (6Klarlund J.K. Guilherme A. Holik J.J. Virbasius J.V. Chawla A. Czech M.P. Science. 1997; 275: 1927-1930Crossref PubMed Scopus (371) Google Scholar). 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. PtdIns-3-P is constitutively present in both mammalian and yeast cells (7Auger K.R. Serunian L.A. Soltoff S.P. Libby P. Cantley L.C. Cell. 1989; 57: 167-175Abstract Full Text PDF PubMed Scopus (683) Google Scholar, 8Auger K.R. Carpenter C.L. Cantley L.C. Varticovski L. J. Biol. Chem. 1989; 264: 20181-20184Abstract Full Text PDF PubMed Google Scholar). 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 (9Vanhaesebroeck B. Leevers S.J. Panayotou G. Waterfield M.D. Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (833) Google Scholar). The mammalian Class III enzyme is highly related to the yeast Vps34 gene product (10Stack J.H. Horazdovsky B. Emr S.D. Annu. Rev. Cell Dev. Biol. 1995; 11: 1-33Crossref PubMed Scopus (172) Google Scholar) and, like the yeast enzyme, is specific for PtdIns and will not phosphorylate PtdIns-4-P or PtdIns-4,5-P2 (11Volinia S. Dhand R. Vanhaesebroeck B. MacDougall L.K. Stein R. Zvelebil M.J. Domin J. Panaretou C. Waterfield M.D. EMBO J. 1995; 14: 3339-3348Crossref PubMed Scopus (309) Google Scholar). 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 (15Patki V. Lawe D.C. Corvera S. Virbasius J.V. Chawla A. Nature. 1998; 394: 433-434Crossref PubMed Scopus (250) Google Scholar, 16Burd C.G. Emr S.D. Mol. Cell. 1998; 2: 157-162Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 17Gaullier J.M. Simonsen A. D'Arrigo A. Bremnes B. Stenmark H. Aasland R. Nature. 1998; 394: 432-433Crossref PubMed Scopus (444) Google Scholar). 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 (16Burd C.G. Emr S.D. Mol. Cell. 1998; 2: 157-162Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 17Gaullier J.M. Simonsen A. D'Arrigo A. Bremnes B. Stenmark H. Aasland R. Nature. 1998; 394: 432-433Crossref PubMed Scopus (444) Google Scholar). Moreover, mutations in the basic motif also eliminated binding (16Burd C.G. Emr S.D. Mol. Cell. 1998; 2: 157-162Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). 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 (17Gaullier J.M. Simonsen A. D'Arrigo A. Bremnes B. Stenmark H. Aasland R. Nature. 1998; 394: 432-433Crossref PubMed Scopus (444) Google Scholar,18Stenmark H. Aasland R. Toh B.H. D'Arrigo A. J. Biol. Chem. 1996; 271: 24048-24054Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar) and on PI 3-K activity (based on wortmannin effects in mammalian cells) (19Patki V. Virbasius J. Lane W.S. Toh B.H. Shpetner H.S. Corvera S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7326-7330Crossref PubMed Scopus (202) Google Scholar). When overexpressed in cells, the FYVE domain of EEA1 is sufficient to determine subcellular localization (16Burd C.G. Emr S.D. Mol. Cell. 1998; 2: 157-162Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). Simonsen and colleagues (20Simonsen A. Lippe R. Christoforidis S. Gaullier J.M. Brech A. Callaghan J. Toh B.H. Murphy C. Zerial M. Stenmark H. Nature. 1998; 394: 494-498Crossref PubMed Scopus (918) Google Scholar, 21.Deleted in proof.Google Scholar) 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. 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. 10Stack J.H. Horazdovsky B. Emr S.D. Annu. Rev. Cell Dev. Biol. 1995; 11: 1-33Crossref PubMed Scopus (172) Google Scholar). 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 (22Brown W.J. DeWald D.B. Emr S.D. Plutner H. Balch W.E. J. Cell Biol. 1995; 130: 781-796Crossref PubMed Scopus (251) Google Scholar, 23Davidson H.W. J. Cell Biol. 1995; 130: 797-805Crossref PubMed Scopus (184) Google Scholar). 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 (12Joly M. Kazlauskas A. Corvera S. J. Biol. Chem. 1995; 270: 13225-13230Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). 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 (20Simonsen A. Lippe R. Christoforidis S. Gaullier J.M. Brech A. Callaghan J. Toh B.H. Murphy C. Zerial M. Stenmark H. Nature. 1998; 394: 494-498Crossref PubMed Scopus (918) Google Scholar, 24Mills I.G. Jones A.T. Clague M.J. Curr. Biol. 1998; 8: 881-884Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). 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. 14Wiedemann C. Cockcroft S. Nature. 1998; 394: 426-427Crossref PubMed Scopus (74) Google Scholar). 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 (7Auger K.R. Serunian L.A. Soltoff S.P. Libby P. Cantley L.C. Cell. 1989; 57: 167-175Abstract Full Text PDF PubMed Scopus (683) Google Scholar, 13Stephens L.R. Hughes K.T. Irvine R.F. Nature. 1991; 351: 33-39Crossref PubMed Scopus (388) Google Scholar, 25Hawkins P.T. Jackson T.R. Stephens L.R. Nature. PubMed Scopus Google Scholar). Stephens and P.T. Jackson T.R. Stephens L.R. Nature. PubMed Scopus Google Scholar) have that the in PtdIns-3,4-P2 levels in these cells is by the 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 PtdIns-3,4-P2 can also be by phosphorylation of the 4-position of PtdIns-3-P by an PtdIns-3-P H. Chen C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the called can catalyze this in is that this enzyme is for the of PtdIns-3,4-P2 levels in because PtdIns-3-P is a for this enzyme with Duckworth Cantley L.C. Nature. 1997; PubMed Scopus Google Scholar). The PI 3-Ks can phosphorylate PtdIns-4-P to of (Fig. 1). The contribution of this pathway to the levels of PtdIns-3,4-P2 is In is that mammalian cells have a of for the levels of PtdIns-3,4-P2 and The protein kinase also as is the most well characterized of The domain of has been shown to phosphoinositides in vitro with the of PtdIns-3,4-P2 PtdIns-3,4,5-P3 PtdIns-4,5-P2 Cantley L.C. A. Science. 1997; 275: PubMed Scopus Google Scholar, M. M. J.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). PtdIns-3,4-P2 binding to causes a stimulation of its activity in vitro Cantley L.C. A. Science. 1997; 275: PubMed Scopus Google Scholar, M. M. J.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). In with PtdIns-3,4-P2 than PtdIns-3,4,5-P3 Cantley L.C. A. Science. 1997; 275: PubMed Scopus Google Scholar). with causes PtdIns-3,4-P2 PtdIns-3,4,5-P3 and in H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In vivo, of also depends on the phosphorylation of a and a M. B. P. P. EMBO J. 1996; PubMed Scopus Google Scholar). of these residues was shown to be on PI The kinase also called was recently and on its to catalyze the phosphorylation of of in a P. Curr. Biol. 1997; Full Text Full Text PDF PubMed Google Scholar, Stephens L.R. T. P.T. Science. 1997; PubMed Scopus Google Scholar, M. A. P. MacDougall A. M. Curr. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, L. H. P. J. P.T. Science. 1998; PubMed Scopus Google Scholar). a domain and with to PtdIns-3,4-P2 and PtdIns-3,4,5-P3 L. H. P. J. P.T. Science. 1998; PubMed Scopus Google Scholar). To the mechanism by which these lipids in vivo, a was in which the PI 3-K lipid products are involved in and its kinases to the and also in changes in that and to be phosphorylated by and kinases (reviewed in Cantley L.C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and J. Science. 1998; PubMed Scopus Google Scholar). can also phosphorylate the of M. A. P. MacDougall A. M. Curr. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. G. Science. 1998; PubMed Scopus Google Scholar) and family members J. L.K. Chen C.-S. A. Curr. Biol. 1998; 8: Full Text Full Text PDF PubMed Google Scholar, D.B. P. Science. 1998; PubMed Scopus Google Scholar) in In most phosphorylation at the of these kinases is necessary for phosphorylation of residues is also for in and from are by PtdIns-3,4-P2 and PtdIns-3,4,5-P3 A. M. J.R. R. S. A. Cantley L.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, H. J.H. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). It is that the activity of these is by phosphorylation and as well as by a direct interaction with these phosphoinositides with these in vitro inhibition of PI 3-K blocks PDGF and of in J. Kazlauskas A. J. Nature. PubMed Scopus Google Scholar), of in L. P. G. J. J. Biol. Chem. 1997; PubMed Scopus Google Scholar, R. G. Mol. Cell. Biol. 1997; PubMed Google Scholar), and and of in S. Kazlauskas A. S. T. S. S. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus (167) Google Scholar). However, the activity of is not on phosphoinositides J. Curr. Biol. 1998; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). the of PI 3-K for phosphorylation of probably a role for PtdIns-3,4,5-P3 in and its at specific of the of cell signals. can phosphorylate and a protein involved in cell (reviewed by Ref. Cantley L.C. Nature. 1997; PubMed Scopus Google Scholar). In addition to have targets that cell because of cells that H. S. H. 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In mammalian cells, the levels of with and with In can also be generated through phosphorylation of the lipid by the Class PI 3-K Duckworth Cantley L.C. Nature. 1997; PubMed Scopus Google Scholar). is a and direct for this lipid has been proteins are for studies of lipid binding specificity of domains not this mutations in the cause of the vacuole A. DeWald D.B. Emr S.D. Mol. Biol. Cell. 1995; PubMed Scopus Google Scholar), be involved in vesicle trafficking (reviewed by Emr and colleagues Emr S.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google The majority of the in to extracellular most generated by phosphorylation of PtdIns-4,5-P2 at the 3-position of the inositol ring P.T. Jackson T.R. Stephens L.R. Nature. PubMed Scopus Google Scholar). 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B. 1997; PubMed Scopus Google Scholar, H. H.S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). The gene the has now been by two L. Cantley L.C. Science. PubMed Scopus Google Scholar, H. M. S. T. S. Science. PubMed Scopus Google Scholar). in cell development and were in both This the of the that PtdIns-3,4,5-P3 of is to cell functions in L. Cantley L.C. Science. PubMed Scopus Google Scholar, H. M. S. T. S. Science. PubMed Scopus Google Scholar). PI 3-K is a specificity kinase that can phosphorylate and residues in addition to phosphoinositide lipids C.L. Auger K.R. Duckworth B. Cantley L.C. Mol. Cell. Biol. 1993; PubMed Scopus Google Scholar, P. P. P. Panayotou G. M.J. S.J. A. Waterfield M.D. Biochem. J. 1993; PubMed Scopus Google Scholar). can phosphorylate the associated regulatory and the receptor (reviewed in Cantley L.C. Annu. Rev. Biochem. 1998; PubMed Scopus Google Scholar). phosphorylation of by PI 3-K the lipid kinase activity of the was that the protein kinase to PI 3-K has a regulatory function. The that the protein kinase activity of PI 3-K a role in is suggested by a recent T. L. G. R. M.P. Science. 1998; PubMed Scopus Google Scholar) have now by a PI protein that has protein kinase activity lipid kinase Moreover, PI was to that the for PI 3-K protein kinase is not at the cell the this enzyme to consistent with on PtdIns-3,4-P2 PtdIns-3,4,5-P3 synthesis T. L. G. R. M.P. Science. 1998; PubMed Scopus Google Scholar). that PI that to or of the pathway be an mechanism by which PI 3-K the of signals. that PI 3-K is involved in different cellular to a of different and that several different proteins are direct targets for phosphoinositides (Fig. an important is specificity in of specificity be by synthesis of different lipid products by different PI 3-K of specificity can be by of PI 3-K to specific subcellular and a in of lipids a specific be EEA1 by PtdIns-3-P and is that the specificity of the is by of two by a specific by PtdIns-3,4,5-P3 and As targets for PI 3-K lipids are the of the of PI 3-K will and for the critical review of this
Source: Journal of Biological Chemistry
Authors: Lucia E. Rameh, Lewis C. Cantley
Institutions: Beth Israel Deaconess Medical Center, Harvard University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2002127663