蛋白磷酸酶2A影响胰岛素调节的研究进展
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摘要
胰岛素分泌以及胰岛素信号通路中涉及大量的蛋白磷酸化与去磷酸化,蛋白磷酸酶2A(protein phosphatase 2A, PP2A)作为真核生物细胞内主要的丝氨酸/苏氨酸磷酸酶,在代谢疾病发生中的作用越来越受到关注。截至目前的研究表明, PP2A可以影响胰岛素的分泌以及周边组织对胰岛素的应答,胰岛素也能够影响PP2A的活性与蛋白水平, PP2A与胰岛素抵抗的关系近年来也成为研究的热点。该文对PP2A在机体胰岛素调节中的作用研究作一综述,希望有助于研究者们对此有更好的认识。
Numerous protein phosphorylation and dephosphorylation are involved in insulin secretion and insulin signaling pathway.Protein phosphatase 2A(PP2A) is one of the most abundant serine/threonine phosphatases in eukaryotic cells,and its role in metabolic disease is given more and more attention.So far,studies have shown that PP2A affects the secretion of insulin and the response of peripheral tissues to insulin,insulin also affects the activity and protein level of PP2A.The relationship between PP2A and insulin resistance has also become a hot topic in recent years.This article reviews the role of PP2A in insulin regulation,which might help to give researchers a further understanding of its important role in insulin regulation.
Numerous protein phosphorylation and dephosphorylation are involved in insulin secretion and insulin signaling pathway.Protein phosphatase 2A(PP2A) is one of the most abundant serine/threonine phosphatases in eukaryotic cells,and its role in metabolic disease is given more and more attention.So far,studies have shown that PP2A affects the secretion of insulin and the response of peripheral tissues to insulin,insulin also affects the activity and protein level of PP2A.The relationship between PP2A and insulin resistance has also become a hot topic in recent years.This article reviews the role of PP2A in insulin regulation,which might help to give researchers a further understanding of its important role in insulin regulation.
引文
1 Wlodarchak N,Xing Y.PP2A as a master regulator of the cell cycle.Crit Rev Biochem Mol Biol 2016;51(3):162-84.
2 Bevan P.Insulin signalling.J Cell Sci 2001;114(Pt 8):1429-30.
3 Sents W,Ivanova E,Lambrecht C,Haesen D,Janssens V.The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity.FEBSJ 2013;280(2):644-61.
4 Seshacharyulu P,Pandey P,Datta K,Batra SK.Phosphatase:PP2A structural importance,regulation and its aberrant expression in cancer.Cancer Lett 2013;335(1):9-18.
5 Perrotti D,Neviani P.Protein phosphatase 2A:a target for anticancer therapy.Lancet Oncol 2013;14(6):e229-38.
6 Hojlund K,Poulsen M,Staehr P,Brusgaard K,Beck-Nielsen H.Effect of insulin on protein phosphatase 2A expression in muscle in type 2 diabetes.Eur J Clin Invest 2002;32(12):918-23.
7 Kowluru A,Matti A.Hyperactivation of protein phosphatase 2Ain models of glucolipotoxicity and diabetes:potential mechanisms and functional consequences.Biochem Pharmacol 2012;84(5):591-7.
8 Beg M,Srivastava A,Shankar K,Varshney S,Rajan S,Gupta A,et al.PPP2R5B,a regulatory subunit of PP2A,contributes to adipocyte insulin resistance.Mol Cell Endocrinol 2016;437:97-107.
9 Galbo T,Olsen GS,Quistorff B,Nishimura E.Free fatty acidinduced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.PLoS One 2011;6(11):e27424.
10 Ammon HP,Heurich RO,Kolb HA,Lang F,Schaich R,Drews G,et al.The phosphatase inhibitor okadaic acid blocks KCl-depolarization-induced rise of cytosolic calcium of rat insulinoma cells(RINm5F).Naunyn Schmiedebergs Arch Pharmacol 1996;354(2):95-101.
11 Jangati GR,Veluthakal R,Susick L,Gruber SA,Kowluru A.Depletion of the catalytic subunit of protein phosphatase-2A(PP2Ac)markedly attenuates glucose-stimulated insulin secretion in pancreatic beta-cells.Endocrine 2007;31(3):248-53.
12 Cho IS,Jung M,Kwon KS,Moon E,Cho JH,Yoon KH,et al.Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription.PLoS One2012;7(4):e34860.
13 Palanivel R,Veluthakal R,Kowluru A.Regulation by glucose and calcium of the carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting INS-1 cells.Am JPhysiol Endocrinol Metab 2004;286(6):E1032-41.
14 Lehtihet M,Honkanen RE,Sjoholm A.Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein phosphatases.Biochem Biophys Res Commun 2004;316(3):893-7.
15 Kowluru A,Seavey SE,Rabaglia ME,Nesher R,Metz SA.Carboxylmethylation of the catalytic subunit of protein phosphatase2A in insulin-secreting cells:evidence for functional consequences on enzyme activity and insulin secretion.Endocrinology 1996;137(6):2315-23.
16 Guo J,Qian Y,Xi X,Hu X,Zhu J,Han X.Blockage of ceramide metabolism exacerbates palmitate inhibition of pro-insulin gene expression in pancreatic beta-cells.Mol Cell Biochem 2010;338(1/2):283-90.
17 Lang F,Ullrich S,Gulbins E.Ceramide formation as a target in beta-cell survival and function.Expert Opin Ther Targets 2011;15(9):1061-71.
18 Arora DK,Machhadieh B,Matti A,Wadzinski BE,Ramanadham S,Kowluru A.High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 betacells by increasing the posttranslational carboxylmethylation of its catalytic subunit.Endocrinology 2014;155(2):380-91.
19 Yan L,Guo S,Brault M,Harmon J,Robertson RP,Hamid R,et al.The B55alpha-containing PP2A holoenzyme dephosphorylates FOXO1 in islet beta-cells under oxidative stress.Biochem J2012;444(2):239-47.
20 Ravnskjaer K,Boergesen M,Dalgaard LT,Mandrup S.Glucoseinduced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation.JMol Endocrinol 2006;36(2):289-99.
21 Yan L,Nairn AC,Palfrey HC,Brady MJ.Glucose regulates EF-2phosphorylation and protein translation by a protein phosphatase-2A-dependent mechanism in INS-1-derived 832/13 cells.JBiol Chem 2003;278(20):18177-83.
22 Kowluru A.Novel regulatory roles for protein phosphatase-2A in the islet beta cell.Biochem Pharmacol 2005;69(12):1681-91.
23 Taniguchi CM,Emanuelli B,Kahn CR.Critical nodes in signalling pathways:insights into insulin action.Nat Rev Mol Cell Biol2006;7(2):85-96.
24 Sarbassov DD,Guertin DA,Ali SM,Sabatini DM.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science 2005;307(5712):1098-101.
25 Kuo YC,Huang KY,Yang CH,Yang YS,Lee WY,Chiang CW.Regulation of phosphorylation of Thr-308 of Akt,cell proliferation,and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.J Biol Chem2008;283(4):1882-92.
26 Rocher G,Letourneux C,Lenormand P,Porteu F.Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.J Biol Chem 2007;282(8):5468-77.
27 Tobisawa T,Yano T,Tanno M,Miki T,Kuno A,Kimura Y,et al.Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55alpha contributes to enlargement of infarct size by chronic kidney disease.Basic Res Cardiol 2017;112(3):31.
28 Galbo T,Perry RJ,Nishimura E,Samuel VT,Quistorff B,Shulman GI.PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.Aging 2013;5(10):770-81.
29 van der Horst A,Burgering BM.Stressing the role of FoxO proteins in lifespan and disease.Nat Rev Mol Cell Biol 2007;8(6):440-50.
30 Nho RS,Peterson M.Eukaryotic translation initiation factor 4Ebinding protein 1(4EBP-1)function is suppressed by Src and protein phosphatase 2A(PP2A)on extracellular matrix.J Biol Chem 2011;286(37):31953-65.
31 Hahn K,Miranda M,Francis VA,Vendrell J,Zorzano A,Teleman AA.PP2A regulatory subunit PP2A-B’counteracts S6Kphosphorylation.Cell Metab 2010;11(5):438-44.
32 Copps KD,White MF.Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.Diabetologia 2012;55(10):2565-82.
33 Kim B,Oh S,van Golen CM,Feldman EL.Differential regulation of insulin receptor substrate-1 degradation during mannitol and okadaic acid induced apoptosis in human neuroblastoma cells.Cell Signal 2005;17(6):769-75.
34 Liu J,Xu C,Zhang S,Li H,Chen K,Huang P,et al.MicrocystinLR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase.Environ Toxicol 2018;33(1):16-22.
35 Rodgers JT,Vogel RO,Puigserver P.Clk2 and B56beta mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt.Mol Cell 2011;41(4):471-9.
36 Tremblay ML,Giguere V.Phosphatases at the heart of FoxOmetabolic control.Cell Metab 2008;7(2):101-3.
37 Jun HS,Hwang K,Kim Y,Park T.High-fat diet alters PP2A,TC10,and CIP4 expression in visceral adipose tissue of rats.Obesity 2008;16(6):1226-31.
38 Begum N,Ragolia L,Srinivasan M.Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells.Eur J Biochem1996;238(1):214-20.
39 Xian L,Hou S,Huang Z,Tang A,Shi P,Wang Q,et al.Liverspecific deletion of Ppp2calpha enhances glucose metabolism and insulin sensitivity.Aging 2015;7(4):223-32.
40 Cheng YS,Seibert O,Kloting N,Dietrich A,Strassburger K,Fernandez-Veledo S,et al.PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.PLoS Genet 2015;11(10):e1005561.
41 MacKay KB,Tu Y,Young SG,Clarke SG.Circumventing embryonic lethality with Lcmt1 deficiency:generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.PLoSOne 2013;8(6):e65967.
42 Obanda DN,Ribnicky D,Yu Y,Stephens J,Cefalu WT.An extract of Urtica dioica L.mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A(PP2A).Sci Rep 2016;6:22222.
43 Chen TC,Benjamin DI,Kuo T,Lee RA,Li ML,Mar DJ,et al.The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCzeta.Sci Signal 2017;10(489):pii:eaai7905.
44 Bernsmeier C,Calabrese D,Heim MH,Duong HT.Hepatitis Cvirus dysregulates glucose homeostasis by a dual mechanism involving induction of PGC1alpha and dephosphorylation of FoxO1.J Viral Hepat 2014;21(1):9-18.
45 Begum N,Ragolia L.Altered regulation of insulin signaling components in adipocytes of insulin-resistant type II diabetic Goto-Kakizaki rats.Metabolism 1998;47(1):54-62.
46 Begum N,Robinson LJ,Draznin B,Heidenreich KA.Protein phosphatase-1 and-2a activities in cultured fetal chick neurons:differential regulation by insulin and insulin-like growth factor-I.Endocrinology 1993;133(5):2085-90.
47 Srinivasan M,Begum N.Regulation of protein phosphatase 1and 2A activities by insulin during myogenesis in rat skeletal muscle cells in culture.J Biol Chem 1994;269(17):12514-20.
48 Reusch JE,Hsieh P,Klemm D,Hoeffler J,Draznin B.Insulin inhibits dephosphorylation of adenosine 3’,5’-monophosphate response element-binding protein/activating transcription factor-1:effect on nuclear phosphoserine phosphatase-2a.Endocrinology1994;135(6):2418-22.
49 Dylla SJ,Williams JP,Williford J,Hardy RW.Phosphatase activity in rat adipocytes:effects of insulin and insulin resistance.JCell Biochem 2000;77(3):445-54.
2 Bevan P.Insulin signalling.J Cell Sci 2001;114(Pt 8):1429-30.
3 Sents W,Ivanova E,Lambrecht C,Haesen D,Janssens V.The biogenesis of active protein phosphatase 2A holoenzymes:a tightly regulated process creating phosphatase specificity.FEBSJ 2013;280(2):644-61.
4 Seshacharyulu P,Pandey P,Datta K,Batra SK.Phosphatase:PP2A structural importance,regulation and its aberrant expression in cancer.Cancer Lett 2013;335(1):9-18.
5 Perrotti D,Neviani P.Protein phosphatase 2A:a target for anticancer therapy.Lancet Oncol 2013;14(6):e229-38.
6 Hojlund K,Poulsen M,Staehr P,Brusgaard K,Beck-Nielsen H.Effect of insulin on protein phosphatase 2A expression in muscle in type 2 diabetes.Eur J Clin Invest 2002;32(12):918-23.
7 Kowluru A,Matti A.Hyperactivation of protein phosphatase 2Ain models of glucolipotoxicity and diabetes:potential mechanisms and functional consequences.Biochem Pharmacol 2012;84(5):591-7.
8 Beg M,Srivastava A,Shankar K,Varshney S,Rajan S,Gupta A,et al.PPP2R5B,a regulatory subunit of PP2A,contributes to adipocyte insulin resistance.Mol Cell Endocrinol 2016;437:97-107.
9 Galbo T,Olsen GS,Quistorff B,Nishimura E.Free fatty acidinduced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.PLoS One 2011;6(11):e27424.
10 Ammon HP,Heurich RO,Kolb HA,Lang F,Schaich R,Drews G,et al.The phosphatase inhibitor okadaic acid blocks KCl-depolarization-induced rise of cytosolic calcium of rat insulinoma cells(RINm5F).Naunyn Schmiedebergs Arch Pharmacol 1996;354(2):95-101.
11 Jangati GR,Veluthakal R,Susick L,Gruber SA,Kowluru A.Depletion of the catalytic subunit of protein phosphatase-2A(PP2Ac)markedly attenuates glucose-stimulated insulin secretion in pancreatic beta-cells.Endocrine 2007;31(3):248-53.
12 Cho IS,Jung M,Kwon KS,Moon E,Cho JH,Yoon KH,et al.Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription.PLoS One2012;7(4):e34860.
13 Palanivel R,Veluthakal R,Kowluru A.Regulation by glucose and calcium of the carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting INS-1 cells.Am JPhysiol Endocrinol Metab 2004;286(6):E1032-41.
14 Lehtihet M,Honkanen RE,Sjoholm A.Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein phosphatases.Biochem Biophys Res Commun 2004;316(3):893-7.
15 Kowluru A,Seavey SE,Rabaglia ME,Nesher R,Metz SA.Carboxylmethylation of the catalytic subunit of protein phosphatase2A in insulin-secreting cells:evidence for functional consequences on enzyme activity and insulin secretion.Endocrinology 1996;137(6):2315-23.
16 Guo J,Qian Y,Xi X,Hu X,Zhu J,Han X.Blockage of ceramide metabolism exacerbates palmitate inhibition of pro-insulin gene expression in pancreatic beta-cells.Mol Cell Biochem 2010;338(1/2):283-90.
17 Lang F,Ullrich S,Gulbins E.Ceramide formation as a target in beta-cell survival and function.Expert Opin Ther Targets 2011;15(9):1061-71.
18 Arora DK,Machhadieh B,Matti A,Wadzinski BE,Ramanadham S,Kowluru A.High glucose exposure promotes activation of protein phosphatase 2A in rodent islets and INS-1 832/13 betacells by increasing the posttranslational carboxylmethylation of its catalytic subunit.Endocrinology 2014;155(2):380-91.
19 Yan L,Guo S,Brault M,Harmon J,Robertson RP,Hamid R,et al.The B55alpha-containing PP2A holoenzyme dephosphorylates FOXO1 in islet beta-cells under oxidative stress.Biochem J2012;444(2):239-47.
20 Ravnskjaer K,Boergesen M,Dalgaard LT,Mandrup S.Glucoseinduced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation.JMol Endocrinol 2006;36(2):289-99.
21 Yan L,Nairn AC,Palfrey HC,Brady MJ.Glucose regulates EF-2phosphorylation and protein translation by a protein phosphatase-2A-dependent mechanism in INS-1-derived 832/13 cells.JBiol Chem 2003;278(20):18177-83.
22 Kowluru A.Novel regulatory roles for protein phosphatase-2A in the islet beta cell.Biochem Pharmacol 2005;69(12):1681-91.
23 Taniguchi CM,Emanuelli B,Kahn CR.Critical nodes in signalling pathways:insights into insulin action.Nat Rev Mol Cell Biol2006;7(2):85-96.
24 Sarbassov DD,Guertin DA,Ali SM,Sabatini DM.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science 2005;307(5712):1098-101.
25 Kuo YC,Huang KY,Yang CH,Yang YS,Lee WY,Chiang CW.Regulation of phosphorylation of Thr-308 of Akt,cell proliferation,and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.J Biol Chem2008;283(4):1882-92.
26 Rocher G,Letourneux C,Lenormand P,Porteu F.Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.J Biol Chem 2007;282(8):5468-77.
27 Tobisawa T,Yano T,Tanno M,Miki T,Kuno A,Kimura Y,et al.Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55alpha contributes to enlargement of infarct size by chronic kidney disease.Basic Res Cardiol 2017;112(3):31.
28 Galbo T,Perry RJ,Nishimura E,Samuel VT,Quistorff B,Shulman GI.PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.Aging 2013;5(10):770-81.
29 van der Horst A,Burgering BM.Stressing the role of FoxO proteins in lifespan and disease.Nat Rev Mol Cell Biol 2007;8(6):440-50.
30 Nho RS,Peterson M.Eukaryotic translation initiation factor 4Ebinding protein 1(4EBP-1)function is suppressed by Src and protein phosphatase 2A(PP2A)on extracellular matrix.J Biol Chem 2011;286(37):31953-65.
31 Hahn K,Miranda M,Francis VA,Vendrell J,Zorzano A,Teleman AA.PP2A regulatory subunit PP2A-B’counteracts S6Kphosphorylation.Cell Metab 2010;11(5):438-44.
32 Copps KD,White MF.Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.Diabetologia 2012;55(10):2565-82.
33 Kim B,Oh S,van Golen CM,Feldman EL.Differential regulation of insulin receptor substrate-1 degradation during mannitol and okadaic acid induced apoptosis in human neuroblastoma cells.Cell Signal 2005;17(6):769-75.
34 Liu J,Xu C,Zhang S,Li H,Chen K,Huang P,et al.MicrocystinLR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase.Environ Toxicol 2018;33(1):16-22.
35 Rodgers JT,Vogel RO,Puigserver P.Clk2 and B56beta mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt.Mol Cell 2011;41(4):471-9.
36 Tremblay ML,Giguere V.Phosphatases at the heart of FoxOmetabolic control.Cell Metab 2008;7(2):101-3.
37 Jun HS,Hwang K,Kim Y,Park T.High-fat diet alters PP2A,TC10,and CIP4 expression in visceral adipose tissue of rats.Obesity 2008;16(6):1226-31.
38 Begum N,Ragolia L,Srinivasan M.Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells.Eur J Biochem1996;238(1):214-20.
39 Xian L,Hou S,Huang Z,Tang A,Shi P,Wang Q,et al.Liverspecific deletion of Ppp2calpha enhances glucose metabolism and insulin sensitivity.Aging 2015;7(4):223-32.
40 Cheng YS,Seibert O,Kloting N,Dietrich A,Strassburger K,Fernandez-Veledo S,et al.PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.PLoS Genet 2015;11(10):e1005561.
41 MacKay KB,Tu Y,Young SG,Clarke SG.Circumventing embryonic lethality with Lcmt1 deficiency:generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.PLoSOne 2013;8(6):e65967.
42 Obanda DN,Ribnicky D,Yu Y,Stephens J,Cefalu WT.An extract of Urtica dioica L.mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A(PP2A).Sci Rep 2016;6:22222.
43 Chen TC,Benjamin DI,Kuo T,Lee RA,Li ML,Mar DJ,et al.The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCzeta.Sci Signal 2017;10(489):pii:eaai7905.
44 Bernsmeier C,Calabrese D,Heim MH,Duong HT.Hepatitis Cvirus dysregulates glucose homeostasis by a dual mechanism involving induction of PGC1alpha and dephosphorylation of FoxO1.J Viral Hepat 2014;21(1):9-18.
45 Begum N,Ragolia L.Altered regulation of insulin signaling components in adipocytes of insulin-resistant type II diabetic Goto-Kakizaki rats.Metabolism 1998;47(1):54-62.
46 Begum N,Robinson LJ,Draznin B,Heidenreich KA.Protein phosphatase-1 and-2a activities in cultured fetal chick neurons:differential regulation by insulin and insulin-like growth factor-I.Endocrinology 1993;133(5):2085-90.
47 Srinivasan M,Begum N.Regulation of protein phosphatase 1and 2A activities by insulin during myogenesis in rat skeletal muscle cells in culture.J Biol Chem 1994;269(17):12514-20.
48 Reusch JE,Hsieh P,Klemm D,Hoeffler J,Draznin B.Insulin inhibits dephosphorylation of adenosine 3’,5’-monophosphate response element-binding protein/activating transcription factor-1:effect on nuclear phosphoserine phosphatase-2a.Endocrinology1994;135(6):2418-22.
49 Dylla SJ,Williams JP,Williford J,Hardy RW.Phosphatase activity in rat adipocytes:effects of insulin and insulin resistance.JCell Biochem 2000;77(3):445-54.