title: Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output.
abstract: Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Gloria
authors.initials: G
authors.lastname: Reyes
authors.affiliation: Departments of Pharmacology and Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Matt
authors.initials: M
authors.lastname: Niederst
authors.affiliation: Departments of Pharmacology and.
authors.forename: Ksenya
authors.initials: K
authors.lastname: Cohen-Katsenelson
authors.affiliation: Cellular and Molecular Medicine and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stender
authors.affiliation: Departments of Pharmacology and.
authors.forename: Maya T
authors.initials: MT
authors.lastname: Kunkel
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and.
authors.forename: Muhan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Departments of Pharmacology and.
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.affiliation: Departments of Pharmacology and.
authors.forename: Emma
authors.initials: E
authors.lastname: Sierecki
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
authors.affiliation: Cellular and Molecular Medicine and.
authors.forename: Dawid G
authors.initials: DG
authors.lastname: Nowak
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and.
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
authors.affiliation: Cellular and Molecular Medicine and.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: Departments of Pharmacology and anewton@ucsd.edu.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020449:Repetitive Sequences, Amino Acid; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D066246:ErbB Receptors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; C541485:EGFR protein, mouse; C519282:PHLPP1 protein, mouse