Phosphoinositide 3-kinase signaling in the vertebrate retina
2009; Elsevier BV; Volume: 51; Issue: 1 Linguagem: Inglês
10.1194/jlr.r000232
ISSN1539-7262
Autores Tópico(s)Retinal Diseases and Treatments
ResumoThe phosphoinositide (PI) cycle, discovered over 50 years ago by Mabel and Lowell Hokin, describes a series of biochemical reactions that occur on the inner leaflet of the plasma membrane of cells in response to receptor activation by extracellular stimuli. Studies from our laboratory have shown that the retina and rod outer segments (ROSs) have active PI metabolism. Biochemical studies revealed that the ROSs contain the enzymes necessary for phosphorylation of phosphoinositides. We showed that light stimulates various components of the PI cycle in the vertebrate ROS, including diacylglycerol kinase, PI synthetase, phosphatidylinositol phosphate kinase, phospholipase C, and phosphoinositide 3-kinase (PI3K). This article describes recent studies on the PI3K-generated PI lipid second messengers in the control and regulation of PI-binding proteins in the vertebrate retina. The phosphoinositide (PI) cycle, discovered over 50 years ago by Mabel and Lowell Hokin, describes a series of biochemical reactions that occur on the inner leaflet of the plasma membrane of cells in response to receptor activation by extracellular stimuli. Studies from our laboratory have shown that the retina and rod outer segments (ROSs) have active PI metabolism. Biochemical studies revealed that the ROSs contain the enzymes necessary for phosphorylation of phosphoinositides. We showed that light stimulates various components of the PI cycle in the vertebrate ROS, including diacylglycerol kinase, PI synthetase, phosphatidylinositol phosphate kinase, phospholipase C, and phosphoinositide 3-kinase (PI3K). This article describes recent studies on the PI3K-generated PI lipid second messengers in the control and regulation of PI-binding proteins in the vertebrate retina. In the early 1950s, Hokin and Hokin (1Hokin M.R. Hokin L.E. Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices.J. Biol. Chem. 1953; 203: 967-977Abstract Full Text PDF PubMed Google Scholar, 2Hokin L.E. Hokin M.R. Effects of acetylcholine on the turnover of phosphoryl units in individual phospholipids of pancreas slices and brain cortex slices.Biochim. Biophys. Acta. 1955; 18: 102-110Crossref PubMed Google Scholar) discovered that addition of acetylcholine to brain slices stimulated the incorporation of phosphate and inositol but not glycerol into lipids; the major products of this incorporation were phosphatidylinositol (PI) and phosphatidic acid. Subsequent studies defined the reactions of the PI cycle and showed that the initial event was receptor-meditated activation of a phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) to 1,2-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). This increase in lipid synthesis reported by the Hokins was a recovery reaction that rapidly replenished PI separate from de novo PI synthesis. The role of 1,4,5-IP3 was established by Streb et al. (3Streb H. Irvine R.F. Berridge M.J. Schulz I. Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate.Nature. 1983; 306: 67-69Crossref PubMed Google Scholar) in their classic paper that showed elevations in IP3 caused intracellular release of bound calcium. Subsequently, 1,2-DG was found to stimulate protein kinase C (PKC), a serine/threonine kinase that phosphorylates a number of cellular proteins (4Nishizuka Y. Studies and perspectives of protein kinase C.Science. 1986; 233: 305-312Crossref PubMed Google Scholar). Activation of the PLC/PKC cascade affects a variety of cellular events, including secretion, phagocytosis, smooth muscle contraction, proliferation, neurotransmission, and metabolism [see reviews by Rhee (5Rhee S.G. 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Chem. 1989; 264: 20181-20184Abstract Full Text PDF PubMed Google Scholar) discovered the receptor-mediated conversion of PI-4,5-P2 to phosphatidylinositol 3,4,5-trisphosphate (PI-3,4,5-P3) in platelet-derived growth factor (PDGF)-stimulated smooth muscle cells and PI to phosphatidylinositol 3-phosphate (PI-3-P) in yeast. Subsequent studies showed that phosphorylation of the D3-position of the inositol ring by phosphoinositide 3-kinase (PI3K) can be stimulated by several extracellular molecules, including PDGF, insulin, insulin-like growth factor-1 (IGF-1), and nerve growth factor [see reviews by Vanhaesebroeck and Waterfield (9Vanhaesebroeck B. Waterfield M.D. Signaling by distinct classes of phosphoinositide 3-kinases.Exp. Cell Res. 1999; 253: 239-254Crossref PubMed Scopus (727) Google Scholar), and Datta et al. (10Datta S.R. Brunet A. Greenberg M.E. Cellular survival: a play in three Akts.Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3614) Google Scholar)]. The formation of all of these phosphoinositides has been demonstrated in mammalian cells [reviewed by Rameh and Cantley(11Rameh L.E. Cantley L.C. The role of phosphoinositide 3-kinase lipid products in cell function.J. Biol. Chem. 1999; 274: 8347-8350Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar)] and we have shown their formation (except for PI-3-P) in intact rod outer segment membranes (ROSs) prepared from fresh bovine retinas (12Ghalayini A.J. Anderson R.E. Light adaptation of bovine retinas in situ stimulates phosphatidylinositol synthesis in rod outer segments in vitro.Curr. Eye Res. 1995; 14: 1025-1029Crossref PubMed Google Scholar, 13Huang Z. Ghalayini A. Guo X.X. Alvarez K.M. Anderson R.E. Light-mediated activation of diacylglycerol kinase in rat and bovine rod outer segments.J. Neurochem. 2000; 75: 355-362Crossref PubMed Scopus (0) Google Scholar, 14Guo X. Ghalayini A.J. Chen H. Anderson R.E. Phosphatidylinositol 3-kinase in bovine photoreceptor rod outer segments.Invest. Ophthalmol. Vis. Sci. 1997; 38: 1873-1882PubMed Google Scholar, 15Guo X.X. Huang Z. Bell M.W. Chen H. Anderson R.E. Tyrosine phosphorylation is involved in phosphatidylinositol 3-kinase activation in bovine rod outer segments.Mol. Vis. 2000; 6: 216-221PubMed Google Scholar). PIs, as components of phospholipids in the cell membrane, contain a D-myo-inositol head group, a glycerol backbone, and two fatty acids at the C1 and C2 acyl positions of glycerol (Fig. 1A). Phosphorylation of multiple free hydroxyls in the inositol head group generates several phosphorylated PI derivatives. Differential phosphorylation at the 3, 4, and 5 positions allows for the generation of seven distinct phosphoinositides (Fig. 1B). The intracellular levels of the phosphoinositides are controlled by PI-specific kinases and phosphatases that can rapidly convert one phosphoinositide into another (16Martin T.F. Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking.Annu. Rev. Cell Dev. Biol. 1998; 14: 231-264Crossref PubMed Scopus (433) Google Scholar). PI signals regulate signal transduction, cytoskeletal assembly, membrane binding, and fusion that are spatially restricted to specific membrane domains (16Martin T.F. Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking.Annu. Rev. Cell Dev. Biol. 1998; 14: 231-264Crossref PubMed Scopus (433) Google Scholar). The classic work of Grado and Ballou (17Grado C. Ballou C.E. Myo-inositol phosphates from beef brain phosphoinostide.J. Biol. Chem. 1960; 235: C23-C24Abstract Full Text PDF PubMed Google Scholar) characterized phosphatidylinositol 4-phosphate (PI-4-P) and PI-4,5-P2 as D4 phosphoinositides. The discovery that phosphorylation at the D3 hydroxyl of the inositol head group (18Whitman M. Downes C.P. Keeler M. Keller T. Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate.Nature. 1988; 332: 644-646Crossref PubMed Scopus (691) Google Scholar) led to the generation of PI-3-P, phosphatidylinositol 3,4-bisphosphate (PI-3,4-P2), and PI-3,4,5-P3, which are referred to as D3 phosphoinositides, increased this diversity. The formation of all of these phosphoinositides has been demonstrated in mammalian cells (11Rameh L.E. Cantley L.C. The role of phosphoinositide 3-kinase lipid products in cell function.J. Biol. Chem. 1999; 274: 8347-8350Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar). The PI3K pathway is highly conserved among different species, including Drosophilia melangaster, Caenorhabditis elegans, and mammals (9Vanhaesebroeck B. Waterfield M.D. Signaling by distinct classes of phosphoinositide 3-kinases.Exp. Cell Res. 1999; 253: 239-254Crossref PubMed Scopus (727) Google Scholar, 19Vanhaesebroeck B. Leevers S.J. Panayotou G. Waterfield M.D. Phosphoinositide 3-kinases: a conserved family of signal transducers.Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (803) Google Scholar). Studies in Drosophila have established the involvement of this pathway in the regulation of cell size and number (20Brogiolo W. Stocker H. Ikeya T. Rintelen F. Fernandez R. Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.Curr. Biol. 2001; 11: 213-221Abstract Full Text Full Text PDF PubMed Scopus (811) Google Scholar, 21Goberdhan D.C. Paricio N. Goodman E.C. Mlodzik M. Wilson C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway.Genes Dev. 1999; 13: 3244-3258Crossref PubMed Scopus (274) Google Scholar, 22Verdu J. Buratovich M.A. Wilder E.L. Birnbaum M.J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB.Nat. Cell Biol. 1999; 1: 500-506Crossref PubMed Google Scholar). Genetic studies in C. elegans have linked this pathway to regulation of dauer formation. The dauer phenotype is a larval state characterized by developmental arrest and reduced metabolic rate triggered by adverse environmental conditions, including nutrient deprivation and overcrowding. Genetic dissection of the genes involved in this pathway led to the identification of the daf (dauer affected) genes (23Lin K. Dorman J.B. Rodan A. Kenyon C. daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.Science. 1997; 278: 1319-1322Crossref PubMed Scopus (1135) Google Scholar, 24Ogg S. Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway.Mol. Cell. 1998; 2: 887-893Abstract Full Text Full Text PDF PubMed Google Scholar), some of which are homologs of the mammalian components of the insulin-PI3K signaling pathway. PI3K belongs to the large family of PI3K-related kinases or PIKK. Other members of the family include mammalian target of rapamycin (mTOR), ataxia-telangiectasia mutated, ataxia-telangiectasia mutated and RAD3 related, and DNA-dependent protein kinase. All possess the characteristic PI3K-homologus kinase domain and a highly conserved carboxy-terminal tail (25Kuruvilla F.G. Schreiber S.L. The PIK-related kinases intercept conventional signaling pathways.Chem. Biol. 1999; 6: R129-R136Abstract Full Text PDF PubMed Scopus (60) Google Scholar). However, only PI3K is known to have an endogenous lipid substrate. Mammalian cells carry at least eight different genes with significant homology and yeast contains only one PI3K gene (26Engelman J.A. Luo J. Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.Nat. Rev. Genet. 2006; 7: 606-619Crossref PubMed Scopus (2176) Google Scholar). The PI3K enzymes are broadly divided into classes I, II, and III, depending upon their substrate specificity (27Hawkins P.T. Anderson K.E. Davidson K. Stephens L.R. Signalling through Class I PI3Ks in mammalian cells.Biochem. Soc. Trans. 2006; 34: 647-662Crossref PubMed Scopus (425) Google Scholar, 28Stephens L. Smrcka A. Cooke F.T. Jackson T.R. Sternweis P.C. Hawkins P.T. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits.Cell. 1994; 77: 83-93Abstract Full Text PDF PubMed Scopus (486) Google Scholar) (Table 1). The class I PI3K phosphorylates PI-4,5-P2 to produce PI-3,4,5-P3 and class III enzymes produce PI-3-P from PI (16Martin T.F. Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking.Annu. Rev. Cell Dev. Biol. 1998; 14: 231-264Crossref PubMed Scopus (433) Google Scholar, 29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). The activity of class II PI3K is debatable and probably involved in the production of both PI-3,4-P2 and PI-3-P (26Engelman J.A. Luo J. Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.Nat. Rev. Genet. 2006; 7: 606-619Crossref PubMed Scopus (2176) Google Scholar). Existing data suggest that class II and III PI3K may be involved in vesicular trafficking (30Maffucci T. Brancaccio A. Piccolo E. Stein R.C. Falasca M. Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation.EMBO J. 2003; 22: 4178-4189Crossref PubMed Scopus (126) Google Scholar, 31Lindmo K. Stenmark H. Regulation of membrane traffic by phosphoinositide 3-kinases.J. Cell Sci. 2006; 119: 605-614Crossref PubMed Scopus (335) Google Scholar). The class I PI3K is the most characterized and best understood enzyme (29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). Class I PI3K enzymes are heterodimers composed of a catalytic subunit and an adaptor regulatory subunit (32Carpenter C.L. Duckworth B.C. Auger K.R. Cohen B. Schaffhausen B.S. Cantley L.C. Purification and characterization of phosphoinositide 3-kinase from rat liver.J. Biol. Chem. 1990; 265: 19704-19711Abstract Full Text PDF PubMed Google Scholar). Class I catalytic subunits share significant homology and have an apparent molecular weight of p110 kDa and thus are referred to as p110 subunits (32Carpenter C.L. Duckworth B.C. Auger K.R. Cohen B. Schaffhausen B.S. Cantley L.C. Purification and characterization of phosphoinositide 3-kinase from rat liver.J. Biol. Chem. 1990; 265: 19704-19711Abstract Full Text PDF PubMed Google Scholar). There are four class I PI3Kp110 genes known in mammals; these are named Pik3ca, Pik3cb, Pik3cg, and Pik3cd and are referred to as PI3Kα, β, γ, and δ (33Zhao L. Vogt P.K. Class I PI3K in oncogenic cellular transformation.Oncogene. 2008; 27: 5486-5496Crossref PubMed Scopus (413) Google Scholar). Pik3ca and Pik3cb genes are ubiquitously expressed; Pik3cg and Pik3cd genes are specifically found in leukocytes with the exception of Pik3cg, which was recently detected in the cardiovascular system (34Hirsch E. Lembo G. Montrucchio G. Rommel C. Costa C. Barberis L. Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing.Thromb. Haemost. 2006; 95: 29-35Crossref PubMed Scopus (49) Google Scholar). The protein products of these genes have the highest homology at the N-terminal end, and all have a GTPase Ras domain, a C2-lipid binding domain, the phosphatidylinositol kinase domain, and a catalytic domain (35Hirsch E. Costa C. Ciraolo E. Phosphoinositide 3-kinases as a common platform for multi-hormone signaling.J. Endocrinol. 2007; 194: 243-256Crossref PubMed Scopus (0) Google Scholar).TABLE 1PI3K family membersClassCatalytic SubunitRegulatory SubunitActivatorPhosphoinositide Products1ap110αp85RTK, RASPI-3-Pp110βPI-3, 4-P2p110δPI-3,4,5-P31bp110γp101PI-3-PPI-3, 4-P2PI-3,4,5-P3IIPI3KC2 αRTK, integrinsPI-3-PPI3KC2 βPI-3, 4-P2PI3KC2γIIIVSP34pPI-3-P Open table in a new tab In mammals, the PI3K catalytic subunits (p110α, p110β, and p110δ) are bound to any of five distinct regulatory subunits (p85α, p85β, p55γ, p55α, and p50α, collectively referred to as "p85s") (36Geering B. Cutillas P.R. Nock G. Gharbi S.I. Vanhaesebroeck B. Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.Proc. Natl. Acad. Sci. USA. 2007; 104: 7809-7814Crossref PubMed Scopus (0) Google Scholar). These p85 adapters result from three genes: Pik3r1, Pik3r2, and Pik3r3 (35Hirsch E. Costa C. Ciraolo E. Phosphoinositide 3-kinases as a common platform for multi-hormone signaling.J. Endocrinol. 2007; 194: 243-256Crossref PubMed Scopus (0) Google Scholar). The Pik3r1 can be expressed in splice variants that encode p85α, p55α, and p50α. The adapters p85α and p85β are ubiquitously expressed (35Hirsch E. Costa C. Ciraolo E. Phosphoinositide 3-kinases as a common platform for multi-hormone signaling.J. Endocrinol. 2007; 194: 243-256Crossref PubMed Scopus (0) Google Scholar), whereas p50α and p55α are present in fat, muscle, liver, and brain (37Antonetti D.A. Algenstaedt P. Kahn C.R. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain.Mol. Cell. Biol. 1996; 16: 2195-2203Crossref PubMed Google Scholar, 38Inukai K. Anai M. Van Breda E. Hosaka T. Katagiri H. Funaki M. Fukushima Y. Ogihara T. Yazaki Kikuchi Y. Oka Y. Asano T. A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene.J. Biol. Chem. 1996; 271: 5317-5320Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), and p55γ is mainly expressed in the brain (39Pons S. Asano T. Glasheen E. Miralpeix M. Zhang Y. Fisher T.L. Myers Jr., M.G. Sun X.J. White M.F. The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase.Mol. Cell. Biol. 1995; 15: 4453-4465Crossref PubMed Scopus (222) Google Scholar). All members of the p85 family contain a p110-binding region that interacts with a specific domain present at the N-terminal ends of the class IA p110 catalytic domains (40Hiles I.D. Otsu M. Volinia S. Fry M.J. Gout I. Dhand R. Panayotou G. Ruiz-Larrea F. Thompson A. Totty N.F. Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit.Cell. 1992; 70: 419-429Abstract Full Text PDF PubMed Scopus (523) Google Scholar). Phosphorylation of cell surface receptors can be stimulated by several extracellular molecules, including PDGF, insulin, IGF-1, and nerve growth factor (9Vanhaesebroeck B. Waterfield M.D. Signaling by distinct classes of phosphoinositide 3-kinases.Exp. Cell Res. 1999; 253: 239-254Crossref PubMed Scopus (727) Google Scholar, 10Datta S.R. Brunet A. Greenberg M.E. Cellular survival: a play in three Akts.Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3614) Google Scholar). The adaptor subunit of these enzymes contains an Src homology (SH)2-domain that mediates recruitment to phosphotyrosine resides on the cytoplasmic domain of receptors, which results in the activation of the PI3K (29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). Class II enzymes preferentially phosphorylate PI and PI-4-P, but not PI-4,5-P2, in vitro and contain a C2 domain that can mediate membrane interactions (11Rameh L.E. Cantley L.C. The role of phosphoinositide 3-kinase lipid products in cell function.J. Biol. Chem. 1999; 274: 8347-8350Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar, 29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). Evidence also indicates that class 1A PI3Kβ is activated by both G-protein-coupled receptor (GPCR) and tyrosine kinase receptors (41Murga C. Fukuhara S. Gutkind J.S. A novel role for phosphatidylinositol 3-kinase beta in signaling from G protein-coupled receptors to Akt.J. Biol. Chem. 2000; 275: 12069-12073Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The N-terminal p85-binding motif is absent in class IB PI3K and PI3Kγ, but interacts with the p101 (42Stephens L.R. Eguinoa A. Erdjument-Bromage H. Lui M. Cooke F. Coadwell J. Smrcka A.S. Thelen M. Cadwallader K. Tempst P. et al.The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101.Cell. 1997; 89: 105-114Abstract Full Text Full Text PDF PubMed Google Scholar) and p84/87 adaptor for regulation (43Suire S. Coadwell J. Ferguson G.J. Davidson K. Hawkins P. Stephens L. p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma.Curr. Biol. 2005; 15: 566-570Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Voigt P. Brock C. Nurnberg B. Schaefer M. Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma.J. Biol. Chem. 2005; 280: 5121-5127Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The GPCR can activate PI3Kγ and is regulated by free Gβγ subunits of heterotrimeric G proteins, mainly the subtype Gi (34Hirsch E. Lembo G. Montrucchio G. Rommel C. Costa C. Barberis L. Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing.Thromb. Haemost. 2006; 95: 29-35Crossref PubMed Scopus (49) Google Scholar). Class II comprises three members, PI3KC2α, β, and γ, which are characterized by a carboxy-terminal phospholipid-binding domain. Although no regulatory subunit has been identified, class II enzymes are predominantly membrane-bound and activated by membrane receptors including receptor tyrosine kinases and integrins (35Hirsch E. Costa C. Ciraolo E. Phosphoinositide 3-kinases as a common platform for multi-hormone signaling.J. Endocrinol. 2007; 194: 243-256Crossref PubMed Scopus (0) Google Scholar). Class III enzymes, which phosphorylate only PI, are heterodimers of a catalytic subunit associated with the serine/threonine protein kinase adaptor subunit that is required for membrane recruitment (16Martin T.F. Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking.Annu. Rev. Cell Dev. Biol. 1998; 14: 231-264Crossref PubMed Scopus (433) Google Scholar, 29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). The class III kinase, VSP34p, is responsible for producing the majority of the cellular PI-3-P and is involved in protein trafficking through the lysosome. The regulatory p85 subunit contains an SH3 domain capable of binding to proline-rich sequences, a region of homology to the breakpoint cluster region gene product, a p110 binding domain, and two SH2 domains (N and C terminus). The regulatory subunit maintains the p110 catalytic subunit in a low-activity state in quiescent cells and mediates activation by direct interaction with phosphotyrosine residues of activated growth-factor receptors or adaptor proteins (29Fruman D.A. Meyers R.E. Cantley L.C. Phosphoinositide kinases.Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1251) Google Scholar). The activated PI3K converts the plasma membrane lipid PI-4,5-P2 to PI-3,4,5-P3. The termination of PI3K signaling by the degradation of PI-3,4,5-P3 can be mediated by at least two different types of phosphatases. The SH2-containing phosphatases, SHIP1 and SHIP2, dephosphorylate the 5-position of the inositol ring to produce PI-3,4-P2 (45Clement S. Krause U. Desmedt F. Tanti J.F. Behrends J. Pesesse X. Sasaki T. Penninger J. Doherty M. Malaisse W. et al.The lipid phosphatase SHIP2 controls insulin sensitivity.Nature. 2001; 409: 92-97Crossref PubMed Scopus (309) Google Scholar). Although this dephosphorylation impairs some signaling downstream of PI3K, PI-3,4-P2 can also mediate PI3K-dependent responses, and may mediate events that are independent of those stimulated by PI-3,4,5-P3. Loss of SHIP2 causes a dramatic increase in insulin sensitivity, suggesting that this phosphatase critically regulates PI3K signaling downstream of insulin (45Clement S. Krause U. Desmedt F. Tanti J.F. Behrends J. Pesesse X. Sasaki T. Penninger J. Doherty M. Malaisse W. et al.The lipid phosphatase SHIP2 controls insulin sensitivity.Nature. 2001; 409: 92-97Crossref PubMed Scopus (309) Google Scholar). In contrast, the phosphatase PTEN (phosphatase and tensin homolog) dephosphorylates the 3-position of PI-3,4,5-P3 to produce PI-4,5-P2 (46Maehama T. Dixon J.E. PTEN: a tumour suppressor that functions as a phospholipid phosphatase.Trends Cell Biol. 1999; 9: 125-128Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar). The loss of PTEN protein function has been found in a large fraction of advanced cancers, suggesting that uncontrolled signaling through PI3K may contribute to metastatic cancers (47Maehama T. Dixon J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.J. Biol. Chem. 1998; 273: 13375-13378Abstract Full Text Full Text PDF PubMed Scopus (2428) Google Scholar). Class 1A PI3Kα has been extensively studied in the retina and photoreceptors (14Guo X. Ghalayini A.J. Chen H. Anderson R.E. Phosphatidylinositol 3-kinase in bovine photoreceptor rod outer segments.Invest. Ophthalmol. Vis. Sci. 1997; 38: 1873-1882PubMed Google Scholar, 15Guo X.X. Huang Z. Bell M.W. Chen H. Anderson R.E. Tyrosine phosphorylation is involved in phosphatidylinositol 3-kinase activation in bovine rod outer segments.Mol. Vis. 2000; 6: 216-221PubMed Google Scholar, 48Dilly A.K. Rajala R.V. Insulin growth factor 1 receptor/PI3K/AKT survival pathway in outer segment membranes of rod photoreceptors.Invest. Ophthalmol. Vis. Sci. 2008; 49: 4765-4773Crossref PubMed Scopus (22) Google Scholar, 49Rajala A. Anderson R.E. Ma J.X. Lem J. Al Ubaidi M.R. Rajala R.V. G-protein-coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor.J. Biol. Chem. 2007; 282: 9865-9873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 50Rajala R.V. McClellan M.E. Ash J.D. Anderson R.E. In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit.J. Biol. Chem. 2002; 277: 43319-43326Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 51Rajala R.V. Anderson R.E. Interaction of the insulin receptor beta-subunit with phosphatidylinositol 3-kinase in bovine ROS.Invest. Ophthalmol. Vis. Sci. 2001; 42: 3110-3117PubMed Google Scholar, 52Reiter C.E. Sandirasegarane L. Wolpert E.B. Klinger M. Simpson I.A. Barber A.J. Antonetti D.A. Kester M. Gardner T.W. Characterization of insulin signaling in rat retina in vivo and ex vivo.Am. J. Physiol. Endocrinol. Metab. 2003; 285: E763-E774Crossref PubMed Scopus (0) Google Scholar). The retinal transducin βγ subunits can stimulate G-protein-regulated PI3K, presumably PI3Kγ or class 1A PI3Kβ (53Parish C.A. Smrcka A.V. Rando R.R. Functional significance of beta gamma-subunit carboxymethylation for the activation of phospholipase C and phosphoinositide 3-kinase.Biochemistry. 1995; 34: 7722-7727Crossref PubMed Google Scholar). Class III PI3K-generated PI-3-P was found to be involved in the vesicular membrane targeting of rhodopsin (54Chuang J.Z. Zhao Y. Sung C.H. SARA-regulated vesicular targeting underlies formation of the light-sensing organelle in mammalian rods.Cell. 2007; 130: 535-547Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Biochemical and functional studies related to other class of PI3K or different isoforms have yet to be performed on the retina and photoreceptors. The growth factor-stimulated PI3K pathway is described in Fig. 2. PI3K activity increases in response to PDGF binding to its receptor, in a large part because the class IA p85/p110 complex is translocated from the cytosol to the plasma membrane by the direct binding of the p85 SH2 domain to tyrosine-phosphorylated sites on the receptor (55Hu P. Mondino A. Skolnik E.Y. Schlessinger J. Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85.Mol. Cell. Biol. 1993; 13: 7677-7688Crossref PubMed Google Scholar, 56Klippel A. Escobedo J.A. Fantl W.J. Williams L.T. The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor beta receptor.Mol. Cell. Biol. 1992; 12: 1451-1459Crossref PubMed Google Scholar). Insulin receptor (IR) activation stimulates intrinsic tyrosine kinase activity that leads to autophosphorylation. Unlike the epidermal growth factor and PDGF receptors, the phosphorylated IR does not usually directly associate with SH2 proteins (57White M.F. Kahn C.R. The insulin signaling system.J. Biol. Chem. 1994; 269: 1-4Abstract Full Text PDF PubMed Google Scholar). Rather, the activated IR usually phosphorylates insulin receptor substrate (IRS)-1, a principal substrate of the IR, on multiple tyrosine residues, which, in turn, recognizes and binds to th
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