Synonyms
Historical Background
In 1999, Shimuzu et al. identified a novel transcript that oscillated in a circadian-dependent manner in the rat suprachiasmatic nucleus (SCN), a bundle of neurons in the brain responsible for controlling the mammalian circadian clock (Shimizu et al. 1999). Thus, they named this gene product SCN circadian oscillatory protein (SCOP), but the function of the protein encoded by this gene was shrouded in mystery. Six years later, Newton and colleagues identified this same gene in a rational search for a serine/threonine phosphatase responsible for dephosphorylating and inactivating the pro-survival kinase, Akt (Gao et al. 2005). Upon agonist stimulation, Akt is recruited to the plasma membrane by its phosphoinositide-sensing pleckstrin homology (PH) domain, where it becomes phosphorylated by another PH domain-containing kinase, the phosphoinositide-dependent kinase-1 (PDK-1). Hypothesizing that a phosphatase that...
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Andreozzi F, Procopio C, Greco A, Mannino GC, Miele C, Raciti GA, et al. 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.
Bradley EW, Carpio LR, Westendorf JJ. Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem. 2013;288(14):9572–82.
Bradley EW, Carpio LR, McGee-Lawrence ME, Castillejo Becerra C, Amanatullah DF, Ta LE, et al. Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. Osteoarthr Cartil. 2015. doi:10.1016/j.joca.2015.12.014.
Brognard J, Sierecki E, Gao T, Newton AC. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell. 2007;25(6):917–31.
Chen M, Pratt CP, Zeeman ME, Schultz N, Taylor BS, O’Neill A, et al. Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell. 2011;20(2):173–86.
Cozzone D, Frojdo S, Disse E, Debard C, Laville M, Pirola L, et al. Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients. Diabetologia. 2008;51(3):512–21.
Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005;18(1):13–24.
Gao T, Brognard J, Newton AC. The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem. 2008;283(10):6300–11.
Li X, Stevens PD, Liu J, Yang H, Wang W, Wang C, et al. PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice. Gastroenterology. 2014;146(5):1301–12 .e1-10
Liu J, Stevens PD, Li X, Schmidt MD, Gao T. PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol. 2011;31(24):4917–27.
Masubuchi S, Gao T, O’Neill A, Eckel-Mahan K, Newton AC, Sassone-Corsi P. Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock. Proc Natl Acad Sci U S A. 2010;107(4):1642–7.
Matsumoto K, Uno I, Oshima Y, Ishikawa T. Isolation and characterization of yeast mutants deficient in adenylate cyclase and cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1982;79(7):2355–9.
Miyamoto S, Purcell NH, Smith JM, Gao T, Whittaker R, Huang K, et al. PHLPP-1 negatively regulates Akt activity and survival in the heart. Circ Res. 2010;107(4):476–84.
O’Neill AK, Niederst MJ, Newton AC. Suppression of survival signalling pathways by the phosphatase PHLPP. The FEBS Journal. 2013;280(2):572–83.
Qiao M, Wang Y, Xu X, Lu J, Dong Y, Tao W, et al. Mst1 is an interacting protein that mediates PHLPPs’ induced apoptosis. Mol Cell. 2010;38(4):512–23.
Reyes G, Niederst M, Cohen-Katsenelson K, Stender JD, Kunkel MT, Chen M, et al. 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.
Russell M, Bradshaw-Rouse J, Markwardt D, Heideman W. Changes in gene expression in the Ras/adenylate cyclase system of Saccharomyces cerevisiae: correlation with cAMP levels and growth arrest. Mol Biol Cell. 1993;4(7):757–65.
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.
Sierecki E, Newton AC. Biochemical characterization of the phosphatase domain of the tumor suppressor PH domain leucine-rich repeat protein phosphatase. Biochemistry. 2014;53(24):3971–81.
Sierecki E, Sinko W, McCammon JA, Newton AC. Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. J Med Chem. 2010;53(19):6899–911.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this entry
Cite this entry
Grzechnik, A.T., Newton, A.C. (2018). PH Domain Leucine-Rich Repeat Protein Phosphatase (PHLPP). In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101823
Download citation
DOI: https://doi.org/10.1007/978-3-319-67199-4_101823
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67198-7
Online ISBN: 978-3-319-67199-4
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences