title: The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation.
abstract: Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress-responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1.
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: An
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Rhea
authors.initials: R
authors.lastname: Sumpter
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, United States.
authors.forename: Minfei
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zang
authors.affiliation: Department of Chemistry and Biochemistry, North Dakota State University, Fargo, United States.
authors.forename: Sangita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003470:Culture Media; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D003470:Culture Media; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C491997:BECN1 protein, human; C098416:MAP-kinase-activated kinase 3
keywords: BCL2; Beclin 1; MAPK signaling; autophagy; biochemistry; cell biology; human; mouse; starvation