MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability

Nature Communications
Dharmendra DingarLinda Z Penn

Abstract

The c-MYC (MYC) oncoprotein is deregulated in over 50% of cancers, yet regulatory mechanisms controlling MYC remain unclear. To this end, we interrogated the MYC interactome using BioID mass spectrometry (MS) and identified PP1 (protein phosphatase 1) and its regulatory subunit PNUTS (protein phosphatase-1 nuclear-targeting subunit) as MYC interactors. We demonstrate that endogenous MYC and PNUTS interact across multiple cell types and that they co-occupy MYC target gene promoters. Inhibiting PP1 by RNAi or pharmacological inhibition results in MYC hyperphosphorylation at multiple serine and threonine residues, leading to a decrease in MYC protein levels due to proteasomal degradation through the canonical SCFFBXW7 pathway. MYC hyperphosphorylation can be rescued specifically with exogenous PP1, but not other phosphatases. Hyperphosphorylated MYC retained interaction with its transcriptional partner MAX, but binding to chromatin is significantly compromised. Our work demonstrates that PP1/PNUTS stabilizes chromatin-bound MYC in proliferating cells.

References

Aug 1, 1992·The Journal of Cell Biology·B Lüscher, R N Eisenman
Jun 12, 2003·Methods : a Companion to Methods in Enzymology·Jayanta DebnathJoan S Brugge
Jan 30, 2004·Molecular and Cellular Biology·Zhongdong HuangJ Michael Bishop
Feb 21, 2004·Bioinformatics·Robertson Craig, Ronald C Beavis
Mar 6, 2004·Nature·Harith RajagopalanChristoph Lengauer
Sep 22, 2006·The Journal of Biological Chemistry·Jörg VervoortsBernhard Lüscher
Jul 9, 2008·Bioinformatics·Darren KessnerParag Mallick
Aug 22, 2008·Nature·Laura SoucekGerard I Evan
Nov 26, 2008·Nature Reviews. Cancer·Natalie Meyer, Linda Z Penn
Dec 17, 2009·Methods in Molecular Biology·Patrick G A Pedrioli
Apr 20, 2010·Advances in Cancer Research·Ami AlbihnMarie Arsenian Henriksson
Oct 14, 2010·Molecular and Cellular Biochemistry·Marina JerebtsovaSergei Nekhai
Oct 15, 2010·Nature Biotechnology·Guomin LiuAnne-Claude Gingras
Dec 7, 2010·Nature Methods·Hyungwon ChoiAlexey I Nesvizhskii
Jan 29, 2011·Cell Cycle·Manpreet KalkatLinda Penn
Jun 28, 2011·Advances in Cancer Research·Lance R Thomas, William P Tansey
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Jan 10, 2012·Gene·Bernhard Lüscher, Jörg Vervoorts
Apr 3, 2012·Cell·Chi V Dang
Mar 12, 2013·Genes & Development·Laura SoucekGerard I Evan
Apr 4, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ji Young KimMaria T Diaz-Meco
Sep 14, 2013·Cancer Research·Amanda R WasylishenLinda Z Penn
Jan 5, 2014·Cold Spring Harbor Perspectives in Medicine·Maralice Conacci-SorrellRobert N Eisenman
Mar 5, 2014·Cold Spring Harbor Perspectives in Medicine·Amy S Farrell, Rosalie C Sears
Mar 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Meng S ChoyRebecca Page
Mar 25, 2014·Biochimica Et Biophysica Acta·Steven Fletcher, Edward V Prochownik
Jun 4, 2014·Cold Spring Harbor Perspectives in Medicine·Meital GabayDean W Felsher
Jul 8, 2014·Oncogene·A A ChakrabortyW P Tansey
Jul 20, 2014·Biochimica Et Biophysica Acta·Therese Wahlström, Marie Arsenian Henriksson
Dec 3, 2014·Journal of Proteomics·Dharmendra DingarBrian Raught
Dec 6, 2014·Trends in Cell Biology·Elmar WolfDavid L Levens
Feb 24, 2015·Bioinformatics·David Fenyö, Ronald C Beavis
Mar 31, 2015·Molecular Cell·Lance R ThomasWilliam P Tansey
Aug 16, 2015·Cellular Signalling·Sandra RebeloOdete A B da Cruz e Silva
Sep 19, 2015·Cancer Discovery·Zachary E StineChi V Dang
Sep 19, 2015·Nature Reviews. Cancer·Theresia R KressBruno Amati

❮ Previous
Next ❯

Citations

Feb 1, 2020·Expert Opinion on Therapeutic Targets·Daniel Massó-VallésLaura Soucek
Nov 25, 2020·Cellular and Molecular Gastroenterology and Hepatology·Haichuan WangXin Chen
Jan 31, 2021·Cell & Bioscience·Yangfan XuYang Hu
Jun 11, 2021·Frontiers in Cell and Developmental Biology·Ran ZhaoMing Zhou
Jul 1, 2021·Nature Reviews. Cancer·Corey LourencoLinda Z Penn

❮ Previous
Next ❯

Datasets Mentioned

BETA
MSV000082424

Methods Mentioned

BETA
electrophoresis
glycosylation
affinity purification
immunoprecipitation
Assay
ChIP
ChIP-seq
proximity ligation assay
PCR
DamID

Software Mentioned

BioID
R
lattice
SAINT Express
ProHits
MassIVE
Graphpad Prism
Proteowizard
MYC
! Tandem

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.