title: The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity.
abstract: Protein phosphatase type 2A (PP2A) enzymes constitute a large family of Ser/Thr phosphatases with multiple functions in cellular signaling and physiology. The composition of heterotrimeric PP2A holoenzymes, resulting from the combinatorial assembly of a catalytic C subunit, a structural A subunit, and regulatory B-type subunit, provides the essential determinants for substrate specificity, subcellular targeting, and fine-tuning of phosphatase activity, largely explaining why PP2A is functionally involved in so many diverse physiological processes, sometimes in seemingly opposing ways. In this review, we highlight how PP2A holoenzyme biogenesis and enzymatic activity are controlled by a sophisticatedly coordinated network of five PP2A modulators, consisting of α4, phosphatase 2A phosphatase activator (PTPA), leucine carboxyl methyl transferase 1 (LCMT1), PP2A methyl esterase 1 (PME-1) and, potentially, target of rapamycin signaling pathway regulator-like 1 (TIPRL1), which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. Likewise, these modulators may come into play when PP2A holoenzymes are disassembled following particular cellular stresses. Malfunctioning of these cellular control mechanisms contributes to human disease. The potential therapeutic benefits or pitfalls of interfering with these regulatory mechanisms will be briefly discussed.
authors.affiliation: Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Ward
authors.initials: W
authors.lastname: Sents
authors.forename: Elitsa
authors.initials: E
authors.lastname: Ivanova
authors.forename: Caroline
authors.initials: C
authors.lastname: Lambrecht
authors.forename: Dorien
authors.initials: D
authors.lastname: Haesen
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D020035:Holoenzymes / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011497:Protein O-Methyltransferase / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000096:biosynthesis / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020035:Holoenzymes; C490467:IGBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C577326:TIPRL protein, human; C524761:LCMT1 protein, human; D011497:Protein O-Methyltransferase; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C087440:PTPA protein, human