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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E3957-65. doi: 10.1073/pnas.1404221111. Epub 2014 Sep 8.

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output.

Author information

1
Departments of Pharmacology and.
2
Departments of Pharmacology and Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093;
3
Cellular and Molecular Medicine and.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and.
5
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
6
Departments of Pharmacology and anewton@ucsd.edu.

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.

PMID:
25201979
PMCID:
PMC4183331
DOI:
10.1073/pnas.1404221111
[Indexed for MEDLINE]
Free PMC Article

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