p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation

Nature Communications
Bárbara González-TeránGuadalupe Sabio

Abstract

Disrupted organ growth leads to disease development. Hypertrophy underlies postnatal heart growth and is triggered after stress, but the molecular mechanisms involved in these processes are largely unknown. Here we show that cardiac activation of p38γ and p38δ increases during postnatal development and by hypertrophy-inducing stimuli. p38γ/δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, which leads to its degradation and mTOR activation. Hearts from mice lacking one or both kinases are below normal size, have high levels of DEPTOR, low activity of the mTOR pathway and reduced protein synthesis. The phenotype of p38γ/δ(-/-) mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38γ and p38δ. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR. Our results demonstrate that p38γ/δ control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.

References

Aug 1, 1996·Journal of Molecular and Cellular Cardiology·F LiA M Gerdes
May 9, 2000·Methods in Enzymology·W W HauswirthN Muzyczka
Oct 11, 2001·Proceedings of the National Academy of Sciences of the United States of America·P LiaoY Wang
Jun 25, 2002·Genes & Development·Diane C FingarJohn Blenis
Jan 14, 2003·Annual Review of Physiology·N Frey, E N Olson
Apr 2, 2003·Circulation·Tetsuo ShioiSeigo Izumo
May 31, 2003·Circulation Research·Hiroshi Akazawa, Issei Komuro
Dec 5, 2003·Journal of Molecular and Cellular Cardiology·Qiangrong Liang, Jeffery D Molkentin
Apr 7, 2004·Circulation·Norbert FreyJoseph A Hill
Oct 18, 2005·Current Opinion in Cell Biology·Dos D SarbassovDavid M Sabatini
Nov 17, 2005·Molecular and Cellular Biology·Victoria A BeardmoreJ Simon C Arthur
Aug 2, 2006·Biological & Pharmaceutical Bulletin·Yoko KubotaKazumasa Shinozuka
Aug 29, 2006·Nature Reviews. Molecular Cell Biology·Joerg Heineke, Jeffery D Molkentin
Jul 7, 2007·Cancer Cell·David A Guertin, David M Sabatini
Mar 24, 2009·Nature Methods·Enrico K SchmidtPhilippe Pierre
Sep 2, 2009·Molecular and Cellular Biology·Christian C DibbleBrendan D Manning
Sep 22, 2010·Circulation·Aranzazu Cruz-AdaliaPilar Martín
Oct 28, 2010·The Journal of Clinical Investigation·David M PatrickEric N Olson
Dec 15, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Craig A GoodmanTroy A Hornberger
Jul 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ivan del Barco BarrantesAngel R Nebreda
Apr 27, 2012·Physiological Reviews·John M Kyriakis, Joseph Avruch
Sep 21, 2012·Circulation Research·Mannix Auger-MessierJeffery D Molkentin
Dec 4, 2012·The Journal of Clinical Investigation·Bárbara González-TeránGuadalupe Sabio
Dec 22, 2012·Nature Reviews. Molecular Cell Biology·Marjorie MailletJeffery D Molkentin
Nov 2, 2013·The Journal of Clinical Investigation·Christian RiehleE Dale Abel
Feb 1, 2014·Circulation Research·Sebastiano SciarrettaJunichi Sadoshima
Mar 22, 2014·Seminars in Immunology·Guadalupe Sabio, Roger J Davis
Apr 11, 2015·Journal of the American College of Cardiology·Francisco M CruzJuan A Bernal
Sep 13, 2015·Journal of Molecular Endocrinology·Elisa Manieri, Guadalupe Sabio

❮ Previous
Next ❯

Citations

May 6, 2016·Frontiers in Cell and Developmental Biology·Alejandra EscósAna Cuenda
Jul 26, 2016·Frontiers in Cell and Developmental Biology·Marc K Saba-El-LeilSylvain Meloche
Mar 2, 2018·Antioxidants & Redox Signaling·Paul J M WijnkerJolanda van der Velden
Jul 4, 2018·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Johannes WedelDavid M Briscoe
Feb 9, 2018·Circulation Research·Sebastiano SciarrettaJunichi Sadoshima
Feb 12, 2019·British Journal of Pharmacology·Ling Yeong ChiaMasaaki Sato
May 31, 2019·Circulation Research·Paula Ortiz-SánchezEnrique Lara-Pezzi
Aug 10, 2019·Journal of Cardiovascular Development and Disease·Neil A Turner, Nicola M Blythe
Oct 23, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Aminah A LoonatJames E Clark
Aug 22, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Sharon A GeorgeIgor R Efimov
Apr 12, 2019·Nature·Antonia Tomás-LobaGuadalupe Sabio
Mar 14, 2020·Journal of Cardiovascular Development and Disease·Michael J Zeitz, James W Smyth
Oct 12, 2018·Oxidative Medicine and Cellular Longevity·Arun SamiduraiAnindita Das
Apr 20, 2018·Cell Death & Disease·Caixia WangZhenguo Chen
Oct 18, 2020·Nature Reviews. Endocrinology·Ivana NikolicGuadalupe Sabio
Aug 10, 2019·Molecular Cancer Therapeutics·Mario I VegaAlan Lichtenstein
Nov 9, 2019·Trends in Endocrinology and Metabolism : TEM·Jonas R KnudsenErik A Richter
Jan 30, 2021·Cardiovascular Research·Sebastiano SciarrettaJunichi Sadoshima
Oct 15, 2020·International Journal of Molecular Sciences·Rafael Romero-BecerraGuadalupe Sabio
Mar 7, 2021·International Journal of Molecular Sciences·Shasha YinWenjian Gan
Aug 18, 2020·Journal of Structural Biology·Aik-Hong TehTamao Hisano
Apr 25, 2021·Journal of Molecular and Cellular Cardiology·Mary N LatimerMartin E Young
Jun 28, 2021·Journal of Ovarian Research·Periklis KatopodisVladimir Anikin
Sep 21, 2018·Science Translational Medicine·Fabiana CsukasiDeborah Krakow
Nov 11, 2021·PLoS Biology·Ayelén M SantamansGuadalupe Sabio

❮ Previous
Next ❯

Methods Mentioned

BETA
co-immunoprecipitation
ubiquitination
PCR
immunoprecipitation
FACS
transfection

Software Mentioned

Image J

Related Concepts

Related Feeds

Cardiomegaly

Cardiomegaly, known as an enlarged heart, is a multifactorial disease with different pathophysiological mechanisms. Hypertension, pregnancy, exercise-induced and idiopathic causes are some mechanisms of cardiomegaly. Discover the latest research of cardiomegaly here.