Phosphatidylinositol-3 kinase-dependent translational regulation of Id1 involves the PPM1G phosphatase

• Authors: Kaiming Xu, Emory University; Langfang Wang, Emory University; Wei Feng, Emory University; Yue Feng, Emory University; Hui-Kuo Shu, Emory University
• Journal Title: Oncogene
• Volume: Volume 35, Number 44
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B | 2016-04-11, Pages 5807-5816
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/onc.2016.115
• Subjects: Health Sciences, Oncology; Biology, Molecular; Biology, Genetics

Abstract

Id1 is a helix-loop-helix transcriptional modulator that increases the aggressiveness of malignant glial neoplasms. Since most glioblastomas (GBMs) show increased phosphatidylinositol-3 kinase (PI-3K) signaling, we sought to determine whether this pathway regulates Id1 expression. Higher basal Id1 expression correlates with dysregulated PI-3K signaling in multiple established GBM cell lines. Further characterization of PI-3K-dependent Id1 regulation reveals that chemical or genetic inhibition of PI-3K signaling reduces Id1 protein but not mRNA expression. Overall, PI-3K signaling appears to enhance Id1 translation with no significant effect on its stability. PI-3K signaling is known to regulate protein translation through mTORC1-dependent phosphorylation of 4E-BP1, which reduces its association with and inhibition of the translation initiation factor eIF4E. Interestingly, while inhibition of PI-3K and AKT lowers 4E-BP1 phosphorylation and expression of Id1 in all cases, inhibition of TORC1 with rapamycin does not consistently have a similar effect, suggesting an alternative mechanism for PI-3K-dependent regulation of Id1 translation. We now identify a potential role for the serine–threonine phosphatase PPM1G in translational regulation of Id1 protein expression. PPM1G knockdown by siRNA increase both 4E-BP1 phosphorylation and Id1 expression and PPM1G and 4E-BP1 co-associates in GBM cells. Furthermore, PPM1G is a phosphoprotein and this phosphorylation appears to be regulated by PI-3K activity. Finally, PI-3K inhibition increases PPM1G activity when assessed by an in vitro phosphatase assay. Our findings provide the first evidence that the PI-3K/AKT signaling pathway modulates PPM1G activity resulting in a shift in the balance between hyper- and hypo-phosphorylated 4E-BP1 and translational regulation of Id1 expression.Oncogene advance online publication, 11 April 2016; doi:10.1038/onc.2016.115.