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

Reyes, G., Niederst, M., Cohen-Katsenelson, K., Stender, J. D., Kunkel, M. T., Chen, M., Brognard, J., Sierecki, E., Gao, T., Nowak, D. G., Trotman, L. C., Glass, C. K., Newton, A. C. (September 2014) Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output. Proc Natl Acad Sci U S A, 111 (38). E3957-E3965. ISSN 0027-8424

[img]
Preview
PDF (Paper)
Trotman PNAS 2014.pdf - Published Version

Download (1379Kb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/25201979
DOI: 10.1073/pnas.1404221111

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein phosphatase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Animal Services
CSHL labs > Trotman lab
CSHL Cancer Center Shared Resources > Bioinformatics Service
Depositing User: Matt Covey
Date: 8 September 2014
Date Deposited: 24 Sep 2014 14:21
Last Modified: 08 Nov 2017 20:38
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30811

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving