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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Emerging roles of PHLPP phosphatases in metabolism

  • Cha, Jong-Ho (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Jeong, Yelin (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Oh, Ah-Reum (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Lee, Sang Bae (Division of Life Sciences, Jeonbuk National University: Sarcopenia Total Solution Center) ;
  • Hong, Soon-Sun (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Kim, KyeongJin (Department of Biomedical Sciences, College of Medicine, Inha University)
  • Received : 2021.06.17
  • Accepted : 2021.07.27
  • Published : 2021.09.30
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Abstract

Over the last decades, research has focused on the role of pleckstrin homology (PH) domain leucine-rich repeat protein phosphatases (PHLPPs) in regulating cellular signaling via PI3K/Akt inhibition. The PKB/Akt signaling imbalances are associated with a variety of illnesses, including various types of cancer, inflammatory response, insulin resistance, and diabetes, demonstrating the relevance of PHLPPs in the prevention of diseases. Furthermore, identification of novel substrates of PHLPPs unveils their role as a critical mediator in various cellular processes. Recently, researchers have explored the increasing complexity of signaling networks involving PHLPPs whereby relevant information of PHLPPs in metabolic diseases was obtained. In this review, we discuss the current knowledge of PHLPPs on the well-known substrates and metabolic regulation, especially in liver, pancreatic beta cell, adipose tissue, and skeletal muscle in relation with the stated diseases. Understanding the context-dependent functions of PHLPPs can lead to a promising treatment strategy for several kinds of metabolic diseases.

Keywords

Acknowledgement

This work was supported by the National Research Foundation (NRF) grant funded by the Korea government (MSIT) (No. 2020R1C1C1005631 to JHC, 2020R1C1C1014281 to SBL, 2021R1A5A8029876 to SBL, 2020R1C1C1004015 to KK and 2021R1A5A2031612 to SSH and KK) and INHA UNIVERSITY Research Grant (JHC and KK).

References

  1. Shimizu K, Okada M, Takano A and Nagai K (1999) SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus. FEBS Lett 458, 363-369 https://doi.org/10.1016/S0014-5793(99)01190-4
  2. Gao T, Furnari F and Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18, 13-24 https://doi.org/10.1016/j.molcel.2005.03.008
  3. Brognard J and Newton AC (2008) PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab 19, 223-230 https://doi.org/10.1016/j.tem.2008.04.001
  4. Brognard J, Sierecki E, Gao T and Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25, 917-931 https://doi.org/10.1016/j.molcel.2007.02.017
  5. Baffi TR, Cohen-Katsenelson K and Newton AC (2021) PHLPPing the script: emerging roles of PHLPP phosphatases in cell signaling. Annu Rev Pharmacol Toxicol 61, 723-743 https://doi.org/10.1146/annurev-pharmtox-031820-122108
  6. Mendoza MC and Blenis J (2007) PHLPPing it off: phosphatases get in the Akt. Mol Cell 25, 798-800 https://doi.org/10.1016/j.molcel.2007.03.007
  7. Molina JR, Agarwal NK, Morales FC et al (2012) PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene 31, 1264-1274 https://doi.org/10.1038/onc.2011.324
  8. Reyes G, Niederst M, Cohen-Katsenelson K et al (2014) Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci U S A 111, E3957-3965
  9. Ohwada W, Tanno M, Yano T et al (2020) Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1. Biochim Biophys Acta Mol Basis Dis 1866, 165851 https://doi.org/10.1016/j.bbadis.2020.165851
  10. Aviv Y and Kirshenbaum LA (2010) Novel phosphatase PHLPP-1 regulates mitochondrial Akt activity and cardiac cell survival. Circ Res 107, 448-450 https://doi.org/10.1161/CIRCRESAHA.110.225896
  11. Brazil DP and Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26, 657-664 https://doi.org/10.1016/S0968-0004(01)01958-2
  12. Gao T, Brognard J and Newton AC (2008) The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem 283, 6300-6311 https://doi.org/10.1074/jbc.M707319200
  13. Tovell H and Newton AC (2021) PHLPPing the balance: restoration of protein kinase C in cancer. Biochem J 478, 341-355 https://doi.org/10.1042/BCJ20190765
  14. Liu J, Stevens PD, Li X, Schmidt MD and Gao T (2011) PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol 31, 4917-4927 https://doi.org/10.1128/MCB.05799-11
  15. Baffi TR, Van AN, Zhao W, Mills GB and Newton AC (2019) Protein kinase C quality control by phosphatase phlpp1 unveils loss-of-function mechanism in cancer. Mol Cell 74, 378-392 e375 https://doi.org/10.1016/j.molcel.2019.02.018
  16. Zhang LL, Cao FF, Wang Y et al (2015) The protein kinase C (PKC) inhibitors combined with chemotherapy in the treatment of advanced non-small cell lung cancer: meta-analysis of randomized controlled trials. Clin Transl Oncol 17, 371-377 https://doi.org/10.1007/s12094-014-1241-3
  17. Hsu AH, Lum MA, Shim KS et al (2018) Crosstalk between PKCalpha and PI3K/AKT signaling is tumor suppressive in the endometrium. Cell Rep 24, 655-669 https://doi.org/10.1016/j.celrep.2018.06.067
  18. Qiao M, Wang Y, Xu X et al (2010) Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis. Mol Cell 38, 512-523 https://doi.org/10.1016/j.molcel.2010.03.017
  19. Burnett PE, Barrow RK, Cohen NA, Snyder SH and Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A 95, 1432-1437 https://doi.org/10.1073/pnas.95.4.1432
  20. Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J and Yonezawa K (1999) Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem 274, 34493-34498 https://doi.org/10.1074/jbc.274.48.34493
  21. Ma XM and Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10, 307-318 https://doi.org/10.1038/nrm2672
  22. Wellbrock C, Karasarides M and Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5, 875-885 https://doi.org/10.1038/nrm1498
  23. Li X, Stevens PD, Liu J et al (2014) PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology 146, 1301-1312 e1301-1310 https://doi.org/10.1053/j.gastro.2014.02.003
  24. Ellwood-Yen K, Graeber TG, Wongvipat J et al (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223-238 https://doi.org/10.1016/S1535-6108(03)00197-1
  25. McKeown MR and Bradner JE (2014) Therapeutic strategies to inhibit MYC. Cold Spring Harb Perspect Med 4, a014266 https://doi.org/10.1101/cshperspect.a014266
  26. Nowak DG, Katsenelson KC, Watrud KE et al (2019) The PHLPP2 phosphatase is a druggable driver of prostate cancer progression. J Cell Biol 218, 1943-1957 https://doi.org/10.1083/jcb.201902048
  27. Chang DW, Claassen GF, Hann SR and Cole MD (2000) The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals. Mol Cell Biol 20, 4309-4319 https://doi.org/10.1128/MCB.20.12.4309-4319.2000
  28. Hemann MT, Bric A, Teruya-Feldstein J et al (2005) Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436, 807-811 https://doi.org/10.1038/nature03845
  29. Schwartz JP and Jungas RL (1971) Studies on the hormone-sensitive lipase of adipose tissue. J Lipid Res 12, 553-562 https://doi.org/10.1016/S0022-2275(20)39474-8
  30. Kim K, Kang JK, Jung YH et al (2021) Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver. Nat Commun 12, 1822 https://doi.org/10.1038/s41467-021-22106-2
  31. Chang RM, Yang H, Fang F, Xu JF and Yang LY (2014) MicroRNA-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting PH domain and leucine-rich repeat protein phosphatase. Hepatology 60, 1251-1263 https://doi.org/10.1002/hep.27221
  32. Cai J, Fang L, Huang Y et al (2013) miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer. Cancer Res 73, 5402-5415 https://doi.org/10.1158/0008-5472.CAN-13-0297
  33. Gao G, Kun T, Sheng Y et al (2013) SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells. Mol Biol Rep 40, 2947-2953 https://doi.org/10.1007/s11033-012-2363-8
  34. Li X, Stevens PD, Yang H et al (2013) The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. Oncogene 32, 471-478 https://doi.org/10.1038/onc.2012.66
  35. Yu Y, Dai M, Lu A, Yu E and Merlino G (2018) PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation. Oncogene 37, 2225-2236 https://doi.org/10.1038/s41388-017-0061-7
  36. O'Hayre M, Niederst M, Fecteau JF et al (2012) Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL). Leukemia 26, 1689-1692 https://doi.org/10.1038/leu.2012.6
  37. Smith AJ, Wen YA, Stevens PD, Liu J, Wang C and Gao T (2016) PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells. Oncotarget 7, 7801-7815 https://doi.org/10.18632/oncotarget.6848
  38. Araujo AR, Rosso N, Bedogni G, Tiribelli C and Bellentani S (2018) Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: What we need in the future. Liver Int 38 Suppl 1, 47-51 https://doi.org/10.1111/liv.13643
  39. Loomba R and Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10, 686-690 https://doi.org/10.1038/nrgastro.2013.171
  40. Younossi Z, Anstee QM, Marietti M et al (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15, 11-20 https://doi.org/10.1038/nrgastro.2017.109
  41. Postic C and Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118, 829-838 https://doi.org/10.1172/JCI34275
  42. Kim K and Kim KH (2020) Targeting of secretory proteins as a therapeutic strategy for treatment of nonalcoholic steatohepatitis (NASH). Int J Mol Sci 21, 2296 https://doi.org/10.3390/ijms21072296
  43. Savage DB and Semple RK (2010) Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance. Curr Opin Lipidol 21, 329-336 https://doi.org/10.1097/MOL.0b013e32833b7782
  44. Sarbassov DD, Ali SM, Kim DH et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-in-sensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14, 1296-1302 https://doi.org/10.1016/j.cub.2004.06.054
  45. Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6, 1122-1128 https://doi.org/10.1038/ncb1183
  46. Laplante M and Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149, 274-293 https://doi.org/10.1016/j.cell.2012.03.017
  47. Kim K, Qiang L, Hayden MS, Sparling DP, Purcell NH and Pajvani UB (2016) mTORC1-independent raptor prevents hepatic steatosis by stabilizing PHLPP2. Nat Commun 7, 10255 https://doi.org/10.1038/ncomms10255
  48. Kim K and Pajvani UB (2016) "Free" Raptor - a novel regulator of metabolism. Cell Cycle 15, 1174-1175 https://doi.org/10.1080/15384101.2016.1159835
  49. Kim K, Ryu D, Dongiovanni P et al (2017) Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis. Gastroenterology 153, 1568-1580 e1510 https://doi.org/10.1053/j.gastro.2017.08.039
  50. Weyer C, Bogardus C, Mott DM and Pratley RE (1999) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104, 787-794 https://doi.org/10.1172/JCI7231
  51. Christensen AA and Gannon M (2019) The beta cell in type 2 diabetes. Curr Diab Rep 19, 81 https://doi.org/10.1007/s11892-019-1196-4
  52. Hribal ML, Perego L, Lovari S et al (2003) Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans. FASEB J 17, 1340-1342 https://doi.org/10.1096/fj.02-0685fje
  53. Ye R, Onodera T and Scherer PE (2019) Lipotoxicity and beta cell maintenance in obesity and type 2 diabetes. J Endocr Soc 3, 617-631 https://doi.org/10.1210/js.2018-00372
  54. Elghazi L, Balcazar N and Bernal-Mizrachi E (2006) Emerging role of protein kinase B/Akt signaling in pancreatic betacell mass and function. Int J Biochem Cell Biol 38, 157-163 https://doi.org/10.1016/j.biocel.2005.08.017
  55. Hribal ML, Mancuso E, Arcidiacono GP et al (2020) The phosphatase PHLPP2 plays a key role in the regulation of pancreatic beta-cell survival. Int J Endocrinol 2020, 1027386
  56. Sesti G, Federici M, Lauro D, Sbraccia P and Lauro R (2001) Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms. Diabetes Metab Res Rev 17, 363-373 https://doi.org/10.1002/dmrr.225
  57. Andreozzi F, Procopio C, Greco A et al (2011) Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. Diabetologia 54, 1879-1887 https://doi.org/10.1007/s00125-011-2116-6
  58. Nigro C, Mirra P, Prevenzano I et al (2018) miR-214-dependent increase of PHLPP2 levels mediates the impairment of insulin-stimulated Akt activation in mouse aortic endothelial cells exposed to methylglyoxal. Int J Mol Sci 19, 522 https://doi.org/10.3390/ijms19020522
  59. Sun X, Lin J, Zhang Y et al (2016) MicroRNA-181b improves glucose homeostasis and insulin sensitivity by regulating endothelial function in white adipose tissue. Circ Res 118, 810-821 https://doi.org/10.1161/CIRCRESAHA.115.308166
  60. Mathur A, Pandey VK and Kakkar P (2017) PHLPP: a putative cellular target during insulin resistance and type 2 diabetes. J Endocrinol 233, R185-R198 https://doi.org/10.1530/JOE-17-0081
  61. Xiong X, Wen YA, Mitov MI, M CO, Miyamoto S and Gao T (2017) PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells. Cell Death Discov 3, 16103 https://doi.org/10.1038/cddiscovery.2016.103
  62. Wu J, Dong T, Chen T et al (2020) Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte. Metabolism 103, 154006 https://doi.org/10.1016/j.metabol.2019.154006
  63. Goodyear LJ and Kahn BB (1998) Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49, 235-261 https://doi.org/10.1146/annurev.med.49.1.235
  64. Cozzone D, Frojdo S, Disse E et al (2008) Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients. Diabetologia 51, 512-521 https://doi.org/10.1007/s00125-007-0913-8
  65. Johnson AM and Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152, 673-684 https://doi.org/10.1016/j.cell.2013.01.041
  66. Behera S, Kapadia B, Kain V et al (2018) ERK1/2 activated PHLPP1 induces skeletal muscle ER stress through the inhibition of a novel substrate AMPK. Biochim Biophys Acta Mol Basis Dis 1864, 1702-1716 https://doi.org/10.1016/j.bbadis.2018.02.019
  67. Newton AC and Trotman LC (2014) Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol 54, 537-558 https://doi.org/10.1146/annurev-pharmtox-011112-140338