• 1
    Shimizu K, Okada M, Takano A & Nagai K (1999) SCOP, a novel gene product expressed in a circadian manner in rat suprachiasmatic nucleus. FEBS Lett458, 363369.
  • 2
    Gao T, Furnari F & Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell18, 1324.
  • 3
    Brognard J, Sierecki E, Gao T & Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell25, 917931.
  • 4
    O’Neill A & Newton AC (2009) PHLPP1 (PH domain leucine-rich repeat protein phosphatase 1). Atlas Genet Cytogenet Oncol Haematol, .
  • 5
    Brognard J & Newton AC (2008) PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab19, 223230.
  • 6
    Barford D, Das AK & Egloff MP (1998) The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu Rev Biophys Biomol Struct27, 133164.
  • 7
    Shimizu K, Okada M, Nagai K & Fukada Y (2003) Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of K-Ras in the membrane rafts, negatively regulates MAPK pathway. J Biol Chem278, 1492014925.
  • 8
    Park WS, Heo WD, Whalen JH, O’Rourke NA, Bryan HM, Meyer T & Teruel MN (2008) Comprehensive identification of PIP3-regulated PH domains from C. elegans to H. sapiens by model prediction and live imaging. Mol Cell30, 381392.
  • 9
    Kanan Y, Matsumoto H, Song H, Sokolov M, Anderson RE & Rajala RV (2010) Serine/threonine kinase Akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL. J Neurochem113, 477488.
  • 10
    Gao T, Brognard J & Newton AC (2008) The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem283, 63006311.
  • 11
    Molina JR, Agarwal NK, Morales FC, Hayashi Y, Aldape KD, Cote G & Georgescu MM (2011) PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene.
  • 12
    Jackson TC, Verrier JD, Semple-Rowland S, Kumar A & Foster TC (2010) PHLPP1 splice variants differentially regulate AKT and PKCalpha signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus. J Neurochem115, 941955.
  • 13
    Keranen LM, Dutil EM & Newton AC (1995) Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol5, 13941403.
  • 14
    Tsutakawa SE, Medzihradszky KF, Flint AJ, Burlingame AL & Koshland DE Jr (1995) Determination of in vivo phosphorylation sites in protein kinase C. J Biol Chem270, 2680726812.
  • 15
    Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE & Thomas G (1995) The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J14, 52795287.
  • 16
    Newton AC (2003) Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J370, 361371.
  • 17
    Fayard E, Tintignac LA, Baudry A & Hemmings BA (2005) Protein kinase B/Akt at a glance. J Cell Sci118, 56755678.
  • 18
    Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ & Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell11, 859871.
  • 19
    Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J & Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell127, 125137.
  • 20
    Yang ZZ, Tschopp O, Hemmings-Mieszczak M, Feng J, Brodbeck D, Perentes E & Hemmings BA (2003) Protein kinase B alpha/Akt1 regulates placental development and fetal growth. J Biol Chem278, 3212432131.
  • 21
    Andreozzi F, Procopio C, Greco A, Mannino GC, Miele C, Raciti GA, Ladicicco C, Beguinot F, Pontiroli AE, Hribal ML 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. Diabetologia54, 18791887.
  • 22
    Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM & Gao T (2009) Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene28, 9941004.
  • 23
    Miyamoto S, Purcell NH, Smith JM, Gao T, Whittaker R, Huang K, Castillo R, Glembotski CC, Sussman MA, Newton AC et al. (2010) PHLPP-1 negatively regulates Akt activity and survival in the heart. Circ Res107, 476484.
  • 24
    Suljagic M, Laurenti L, Tarnani M, Alam M, Malek SN & Efremov DG (2010) Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells. Leukemia24, 20632071.
  • 25
    Nitsche C, Edderkaoui M, Moore RM, Eibl G, Kasahara N, Treger J, Grippo PJ, Mayerle J, Lerch MM & Gukovskaya AS (2011) The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology142, 377387.
  • 26
    Chen M, Pratt CP, Zeeman ME, Schultz N, Taylor BS, O’Neill A, Castillo-Martin M, Nowak DG, Naguib A, Grace DM et al. (2011) Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell20, 173186.
  • 27
    Gysin S & Imber R (1997) Phorbol-ester-activated protein kinase C-alpha lacking phosphorylation at Ser657 is down-regulated by a mechanism involving dephosphorylation. Eur J Biochem249, 156160.
  • 28
    Liu J, Stevens PD, Li X, Schmidt MD & Gao T (2011) PHLPP-mediated dephosphorylation of S6K1 inhibits protein translation and cell growth. Mol Cell Biol31, 49174927.
  • 29
    Shimizu K, Phan T, Mansuy IM & Storm DR (2007) Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory. Cell128, 12191229.
  • 30
    Field J, Xu HP, Michaeli T, Ballester R, Sass P, Wigler M & Colicelli J (1990) Mutations of the adenylyl cyclase gene that block RAS function in Saccharomyces cerevisiae. Science247, 464467.
  • 31
    Jang SW, Yang SJ, Srinivasan S & Ye K (2007) Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem282, 3083630844.
  • 32
    Qiao M, Wang Y, Xu X, Lu J, Dong Y, Tao W, Stein J, Stein GS, Iglehart JD, Shi Q et al. (2010) Mst1 is an interacting protein that mediates PHLPPs’ induced apoptosis. Mol Cell38, 512523.
  • 33
    Qiao M, Iglehart JD & Pardee AB (2007) Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res67, 52935299.
  • 34
    Saavedra A, Garcia-Martinez JM, Xifro X, Giralt A, Torres-Peraza JF, Canals JM, Diaz-Hernandez M, Lucas JJ, Alberch J & Perez-Navarro E (2009) PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death Differ17, 324335.
  • 35
    Patterson SJ, Han JM, Garcia R, Assi K, Gao T, O’Neill A, Newton AC & Levings MK (2011) Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol186, 55335537.
  • 36
    Masubuchi S, Gao T, O’Neill A, Eckel-Mahan K, Newton AC & Sassone-Corsi P (2010) Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock. Proc Natl Acad Sci USA107, 16421647.
  • 37
    Lee B, Almad A, Butcher GQ & Obrietan K (2007) Protein kinase C modulates the phase-delaying effects of light in the mammalian circadian clock. Eur J Neurosci26, 451462.
  • 38
    Liu J, Stevens PD & Gao T (2010) mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells. J Biol Chem286, 65106520.
  • 39
    Brognard J, Niederst M, Reyes G, Warfel N & Newton AC (2009) Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem284, 1521515223.
  • 40
    Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ et al. (2003) Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res63, 16081614.
  • 41
    Johnson-Pais TL, Nellissery MJ, Ammerman DG, Pathmanathan D, Bhatia P, Buller CL, Leach RJ & Hansen MF (2003) Determination of a minimal region of loss of heterozygosity on chromosome 18q21.33 in osteosarcoma. Int J Cancer105, 285288.
  • 42
    Patael-Karasik Y, Daniely M, Gotlieb WH, Ben-Baruch G, Schiby J, Barakai G, Goldman B, Aviram A & Friedman E (2000) Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel. Cancer Genet Cytogenet121, 2632.
  • 43
    Rakha EA, Green AR, Powe DG, Roylance R & Ellis IO (2006) Chromosome 16 tumor-suppressor genes in breast cancer. Genes Chromosom Cancer45, 527535.
  • 44
    Safford SD, Goyeau D, Freemerman AJ, Bentley R, Everett ML, Grundy PE & Skinner MA (2003) Fine mapping of Wilms’ tumors with 16q loss of heterozygosity localizes the putative tumor suppressor gene to a region of 6.7 megabases. Ann Surg Oncol10, 136143.
  • 45
    Torring N, Borre M, Sorensen KD, Andersen CL, Wiuf C & Orntoft TF (2007) Genome-wide analysis of allelic imbalance in prostate cancer using the Affymetrix 50K SNP mapping array. Br J Cancer96, 499506.
  • 46
    Tsuda H, Zhang WD, Shimosato Y, Yokota J, Terada M, Sugimura T, Miyamura T & Hirohashi S (1990) Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma. Proc Natl Acad Sci USA87, 67916794.
  • 47
    Hellwinkel OJ, Rogmann JP, Asong LE, Luebke AM, Eichelberg C, Ahyai S, Isbarn H, Graefen M, Huland H & Schlomm T (2008) A comprehensive analysis of transcript signatures of the phosphatidylinositol-3 kinase/protein kinase B signal-transduction pathway in prostate cancer. BJU Int101, 14541460.
  • 48
    Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B et al. (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell18, 1122.
  • 49
    Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, Perry SR, Labrot ES, Wu X, Lis R et al. (2011) SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature470, 269273.
  • 50
    Beezhold K, Liu J, Kan H, Meighan T, Castranova V, Shi X & Chen F (2011) miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicol Sci123, 411420.
  • 51
    Warfel NA, Niederst M, Stevens MW, Brennan PM, Frame MC & Newton AC (2011) Mislocalization of the E3 ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), in the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt. J Biol Chem286, 1977719788.
  • 52
    Li X, Liu J & Gao T (2009) beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. Mol Cell Biol29, 61926205.
  • 53
    Hussain S, Foreman O, Perkins SL, Witzig TE, Miles RR, van Deursen J & Galardy PJ (2010) The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Leukemia24, 16411655.
  • 54
    Pawson CT & Scott JD (2010) Signal integration through blending, bolstering and bifurcating of intracellular information. Nat Struct Mol Biol17, 653658.
  • 55
    Li X, Yang H, Liu J, Schmidt MD & Gao T (2011) Scribble-mediated membrane targeting of PHLPP1 is required for its negative regulation of Akt. EMBO Rep12, 818824.
  • 56
    Teti A, Colucci S, Grano M, Argentino L & Zambonin Zallone A (1992) Protein kinase C affects microfilaments, bone resorption, and [Ca2+]o sensing in cultured osteoclasts. Am J Physiol263, C130C139.
  • 57
    Pei H, Li L, Fridley BL, Jenkins GD, Kalari KR, Lingle W, Petersen G, Lou Z & Wang L (2009) FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell16, 259266.
  • 58
    Mistafa O, Ghalali A, Kadekar S, Hogberg J & Stenius U (2010) Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase, calcineurin, protein phosphatase 2A, and PTEN phosphatases. J Biol Chem285, 2790027910.
  • 59
    Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H et al. (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell19, 575586.
  • 60
    Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S, Plaisier S, Garraway IP, Huang J, Graeber TG et al. (2011) Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell19, 792804.
  • 61
    Gao MH, Miyanohara A, Feramisco JR & Tang T (2009) Activation of PH-domain leucine-rich protein phosphatase 2 (PHLPP2) by agonist stimulation in cardiac myocytes expressing adenylyl cyclase type 6. Biochem Biophys Res Commun384, 193198.
  • 62
    Sowa ME, Bennett EJ, Gygi SP & Harper JW (2009) Defining the human deubiquitinating enzyme interaction landscape. Cell138, 389403.
  • 63
    Sierecki E, Sinko W, McCammon JA & Newton AC (2010) Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. J Med Chem53, 689968911.
  • 64
    Zhang M & Riedel H (2009) Insulin receptor kinase-independent signaling via tyrosine phosphorylation of phosphatase PHLPP1. J Cell Biochem107, 6575.
  • 65
    Courtney KD, Corcoran RB & Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol28, 10751083.
  • 66
    Wong KK, Engelman JA & Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev20, 8790.
  • 67
    Brognard J & Hunter T (2011) Protein kinase signaling networks in cancer. Curr Opin Genet Dev21, 411.
  • 68
    Maehama T & Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem273, 1337513378.
  • 69
    Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R, Kethesparan DS & Mitchell CA (2009) The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J419, 2949.
  • 70
    Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR & Caron MG (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell122, 261273.
  • 71
    Zhao B, Tumaneng K & Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol13, 877883.
  • 72
    Wullschleger S, Loewith R & Hall MN (2006) TOR signaling in growth and metabolism. Cell124, 471484.
  • 73
    Yu Y, Yoon S-O, Poulogiannis G, Yang Q, Ma XM, Villen J, Kubica N, Hoffman GR, Cantley LC, Gygi SP et al. (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science332, 13221326.
  • 74
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R & Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature449, 557563.
  • 75
    Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM & Ganesan S (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell9, 121132.
  • 76
    Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla-Favera R & Califano A (2005) Reverse engineering of regulatory networks in human B cells. Nat Genet37, 382390.
  • 77
    Haslinger C, Schweifer N, Stilgenbauer S, Dohner H, Lichter P, Kraut N, Stratowa C & Abseher R (2004) Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status. J Clin Oncol22, 39373949.
  • 78
    Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K & Malek SN (2008) Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14. Cancer Res68, 10121021.
  • 79
    Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M et al. (2007) Transcriptome profile of human colorectal adenomas. Mol Cancer Res5, 12631275.
  • 80
    Kaiser S, Park YK, Franklin JL, Halberg RB, Yu M, Jessen WJ, Freudenberg J, Chen X, Haigis K, Jegga AG et al. (2007) Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol8, R131.
  • 81
    Gaspar C, Cardoso J, Franken P, Molenaar L, Morreau H, Moslein G, Sampson J, Boer JM, de Menezes RX & Fodde R (2008) Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis. Am J Pathol172, 13631380.
  • 82
    Hao Y, Triadafilopoulos G, Sahbaie P, Young HS, Omary MB & Lowe AW (2006) Gene expression profiling reveals stromal genes expressed in common between Barrett’s esophagus and adenocarcinoma. Gastroenterology131, 925933.
  • 83
    Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD & Sikic BI (2005) High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res65, 40884096.
  • 84
    Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, Atkins D & Wang Y (2005) Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res11, 72347242.
  • 85
    Zhao H, Hao WD, Xu HE, Shang LQ & Lu YY (2004) Gene expression profiles of hepatocytes treated with La(NO3)3 of rare earth in rats. World J Gastroenterol10, 16251629.