Emerging Roles of PHLPP Phosphatases in Metabolism

Overview

Journal BMB Rep

Specialties Biochemistry
Molecular Biology

Date 2021 Aug 6

PMID 34353431

Citations 6

Authors

Jong-Ho Cha

Yelin Jeong

Ah-Reum Oh

Sang Bae Lee

Soon-Sun Hong

KyeongJin Kim

Affiliations

Soon will be listed here.

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. [BMB Reports 2021; 54(9): 451-457].

Citing Articles

Postnatal deletion of Phlpp1 in chondrocytes delays post-traumatic osteoarthritis in male mice.

Weaver S, Arnold K, Peralta-Herrera E, Oviedo M, Zars E, Bradley E Osteoarthr Cartil Open. 2025; 7(1):100525.

PMID: 39811690 PMC: 11732534. DOI: 10.1016/j.ocarto.2024.100525.

Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation.

Weaver S, Peralta-Herrera E, Torres H, Jessen E, Bradley E, Westendorf J Bone. 2024; 189:117265.

PMID: 39349089 PMC: 11549792. DOI: 10.1016/j.bone.2024.117265.

LncRNA CCAT1 knockdown suppresses tongue squamous cell carcinoma progression by inhibiting the ubiquitination of PHLPP2.

Liu F, Yang H, Liu X, Ning Y, Wu Y, Yan X Mol Cell Biochem. 2024; 480(2):1063-1075.

PMID: 38763996 DOI: 10.1007/s11010-024-05004-1.

Mining oomycete proteomes for phosphatome leads to the identification of specific expanded phosphatases in oomycetes.

Qiu M, Sun Y, Tu S, Li H, Yang X, Zhao H Mol Plant Pathol. 2024; 25(3):e13425.

PMID: 38462784 PMC: 10925823. DOI: 10.1111/mpp.13425.

RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling.

Zhu J, Tang J, Wu Y, Qiu X, Jin X, Zhang R Med Oncol. 2023; 40(10):290.

PMID: 37658961 DOI: 10.1007/s12032-023-02137-z.

References

Gao G, Kun T, Sheng Y, Qian M, Kong F, Liu X . SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells. Mol Biol Rep. 2013; 40(4):2947-53. DOI: 10.1007/s11033-012-2363-8. View

Ye R, Onodera T, Scherer P . Lipotoxicity and Cell Maintenance in Obesity and Type 2 Diabetes. J Endocr Soc. 2019; 3(3):617-631. PMC: 6391718. DOI: 10.1210/js.2018-00372. View

Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K . Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem. 1999; 274(48):34493-8. DOI: 10.1074/jbc.274.48.34493. View

Liu J, Stevens P, Li X, Schmidt M, Gao T . PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol. 2011; 31(24):4917-27. PMC: 3233022. DOI: 10.1128/MCB.05799-11. View

Newton A, Trotman L . Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol. 2014; 54:537-58. PMC: 4082184. DOI: 10.1146/annurev-pharmtox-011112-140338. View

Shimizu K, Okada M, Takano A, Nagai K . SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus. FEBS Lett. 1999; 458(3):363-9. DOI: 10.1016/s0014-5793(99)01190-4. View

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

Nowak D, Cohen Katsenelson K, Watrud K, Chen M, Mathew G, DAndrea V . The PHLPP2 phosphatase is a druggable driver of prostate cancer progression. J Cell Biol. 2019; 218(6):1943-1957. PMC: 6548123. DOI: 10.1083/jcb.201902048. View

Li X, Stevens P, Yang H, Gulhati P, Wang W, Evers B . The deubiquitination enzyme USP46 functions as a tumor suppressor by controlling PHLPP-dependent attenuation of Akt signaling in colon cancer. Oncogene. 2012; 32(4):471-8. PMC: 3371166. DOI: 10.1038/onc.2012.66. View

10.

Mathur A, Pandey V, Kakkar P . PHLPP: a putative cellular target during insulin resistance and type 2 diabetes. J Endocrinol. 2017; 233(3):R185-R198. DOI: 10.1530/JOE-17-0081. View

11.

McKeown M, Bradner J . Therapeutic strategies to inhibit MYC. Cold Spring Harb Perspect Med. 2014; 4(10). PMC: 4200208. DOI: 10.1101/cshperspect.a014266. View

12.

Gao T, Furnari F, Newton A . PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005; 18(1):13-24. DOI: 10.1016/j.molcel.2005.03.008. View

13.

Brazil D, Hemmings B . Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 2001; 26(11):657-64. DOI: 10.1016/s0968-0004(01)01958-2. View

14.

Andreozzi F, Procopio C, Greco A, Mannino G, Miele C, Raciti G . 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. 2011; 54(7):1879-87. DOI: 10.1007/s00125-011-2116-6. View

15.

Elghazi L, Balcazar N, Bernal-Mizrachi E . Emerging role of protein kinase B/Akt signaling in pancreatic beta-cell mass and function. Int J Biochem Cell Biol. 2005; 38(2):157-63. DOI: 10.1016/j.biocel.2005.08.017. View

16.

Araujo A, Rosso N, Bedogni G, Tiribelli C, Bellentani S . Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: What we need in the future. Liver Int. 2018; 38 Suppl 1:47-51. DOI: 10.1111/liv.13643. View

17.

Letizia Hribal M, Mancuso E, Arcidiacono G, Greco A, Musca D, Procopio T . The Phosphatase PHLPP2 Plays a Key Role in the Regulation of Pancreatic Beta-Cell Survival. Int J Endocrinol. 2020; 2020:1027386. PMC: 7199632. DOI: 10.1155/2020/1027386. View

18.

Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg M, Hall A . Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004; 6(11):1122-8. DOI: 10.1038/ncb1183. View

19.

Younossi Z, Anstee Q, Marietti M, Hardy T, Henry L, Eslam M . Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2017; 15(1):11-20. DOI: 10.1038/nrgastro.2017.109. View

20.

Reyes G, Niederst M, Cohen-Katsenelson K, Stender J, Kunkel M, Chen M . Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci U S A. 2014; 111(38):E3957-65. PMC: 4183331. DOI: 10.1073/pnas.1404221111. View