title: p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation.
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.
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: González-Terán
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: López
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Rodríguez
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Leiva
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Martínez-Martínez
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Bernal
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.|Hospital de La Princesa, 28006 Madrid, Spain.
authors.forename: Luis Jesús
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vazquez
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, CNIC, 28029 Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Sabio
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C570841:deptor protein, mouse; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases