title: Alpha4 is an essential regulator of PP2A phosphatase activity.
abstract: The activity and specificity of serine/threonine phosphatases are governed largely by their associated proteins. alpha4 is an evolutionarily conserved noncatalytic subunit for PP2A-like phosphatases. Though alpha4 binds to only a minority of PP2A-related catalytic subunits, alpha4 deletion leads to progressive loss of all PP2A, PP4, and PP6 phosphatase complexes. In healthy cells, association with alpha4 renders catalytic (C) subunits enzymatically inactive while protecting them from proteasomal degradation until they are assembled into a functional phosphatase complex. During cellular stress, existing PP2A complexes can become unstable. Under such conditions, alpha4 sequesters released C subunits and is required for the adaptive increase in targeted PP2A activity that can dephosphorylate stress-induced phosphorylated substrates. Consistent with this, overexpression of alpha4 protects cells from a variety of stress stimuli, including DNA damage and nutrient limitation. These findings demonstrate that alpha4 plays a required role in regulating the assembly and maintenance of adaptive PP2A phosphatase complexes.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Kong
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004795:Enzyme Stability / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018869:Heat-Shock Response / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D055503:Protein Multimerization / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C092377:Igbp1 protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse; C080406:protein phosphatase 4; C106079:protein phosphatase 6; C475961:gamma-H2AX protein, mouse