title: The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation.
abstract: Glutamine is an essential nutrient for cancer cell survival and proliferation, yet the signaling pathways that sense glutamine levels remain uncharacterized. Here, we report that the protein phosphatase 2A (PP2A)-associated protein, α4, plays a conserved role in glutamine sensing. α4 promotes assembly of an adaptive PP2A complex containing the B55α regulatory subunit via providing the catalytic subunit upon glutamine deprivation. Moreover, B55α is specifically induced upon glutamine deprivation in a ROS-dependent manner to activate p53 and promote cell survival. B55α activates p53 through direct interaction and dephosphorylation of EDD, a negative regulator of p53. Importantly, the B55α-EDD-p53 pathway is essential for cancer cell survival and tumor growth under low glutamine conditions in vitro and in vivo. This study delineates a previously unidentified signaling pathway that senses glutamine levels as well as provides important evidence that protein phosphatase complexes are actively involved in signal transduction.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, CA 91010, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Reid
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Wang
authors.forename: Kimberly Romero
authors.initials: KR
authors.lastname: Rosales
authors.forename: Meng Xu
authors.initials: MX
authors.lastname: Welliver
authors.forename: Min
authors.initials: M
authors.lastname: Pan
authors.forename: Mei
authors.initials: M
authors.lastname: Kong
mesh_terms: D000222:Adaptation, Physiological; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000172:deficiency*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D015533:Transcriptional Activation; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C092377:Igbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases; C581986:Ppp2r2a protein, mouse; D054648:Protein Phosphatase 2