Back to Search
Start Over
Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 111, iss 38
- Publication Year :
- 2014
- Publisher :
- Proceedings of the National Academy of Sciences, 2014.
-
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.
- Subjects :
- Repetitive Sequences, Amino Acid
Transcription, Genetic
MAP Kinase Signaling System
Knockout
Biology
Models, Biological
Tropomyosin receptor kinase C
Repetitive Sequences
Receptor tyrosine kinase
Cell Line
Mice
Phosphatidylinositol 3-Kinases
Rare Diseases
Genetic
Growth factor receptor
Models
Phosphoprotein Phosphatases
2.1 Biological and endogenous factors
Animals
Aetiology
Protein kinase B
Protein Kinase C
Cancer
Cell Line, Transformed
Mice, Knockout
PHLPP
Multidisciplinary
Nuclear Proteins
Biological
Brain Disorders
Rats
ErbB Receptors
Amino Acid
Transformed
PNAS Plus
ROR1
Cancer research
biology.protein
Transcription
Proto-Oncogene Proteins c-akt
Tyrosine kinase
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 111
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....73a99ebb779e91bddbc219030d76e027