Physiologic functions of PP2A: Lessons from genetically modified mice

Abstract

Protein Phosphatase 2A (PP2A) encompasses a large family of Ser/Thr phosphatases, consisting of a catalytic C subunit and a structural A subunit that are, in most cases, further bound to a regulatory B-type subunit. The B-type subunits determine function and regulation of PP2A trimers, but despite their importance in PP2A biology, their roles in controlling dephosphorylation of a given substrate in a given cell or tissue remain poorly defined, particularly in the context of a complete organism. Besides twenty PP2A subunit encoding genes, some of which are tissue-specifically expressed, five additional genes encode major regulators of active PP2A trimer assembly, and at least seven genes encode cellular PP2A inhibitors, further adding to the complexity of the mammalian PP2A system. In this review, we summarize current knowledge on physiologic functions of PP2A in germ cell maturation, embryonic development, metabolic regulation, tumor suppression, and homeostasis of adult brain, heart, liver, immune system, lung, intestine, kidney, skin, bone and eye, all retrieved from in vivo studies using PP2A transgenic, knockout or knockin mice. Data from 63 mouse models, generated between 1998 and now, reveal the essentiality of PP2A in vivo, and shed light on tissue-specific functions of particular PP2A subunits on the one hand, and functional redundancies on the other hand. In future, it remains of utmost importance to further characterize the existing models, as well as to generate novel models, with the aim of deepening our insights in PP2A (patho)physiology and, particularly, in the therapeutic potential of PP2A targeting in human disease.

The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets

“…Due to the enormous PP2A diversity and possibilities of redundant functions, individual PP2A family members and their regulators/inhibitors need to be studied independently. This is now possible using murine and human genetics [72,[89][90][91], novel selective PP2A inhibitors [62] and cellular models such as human platelets.…”

Benzene-induced mouse hematotoxicity is regulated by a protein phosphatase 2A complex that stimulates transcription of cytochrome P4502E1

“…However, the roles of PP2A in the regulation of dephosphorylation of a given substrate in a given cell or tissue remain largely unknown. Although many PP2A transgenic, knockout, or knock-in mice have been generated (35), few models are available for investigating the tissue-specific functions of par-ticular PP2A subunits. In this study, we generated a mouse model with a hepatocyte-specific deletion of the Ppp2r1a gene (coding PP2A A␣) to clarify the molecular pathways involved in regulation of benzene-induced hemototoxicity.…”

PP2A Regulates Phosphorylation-Dependent Isomerization of Cytoplasmic and Mitochondrial-Associated ATR by Pin1 in DNA Damage Responses

“…This defines PP2A as a potential target in regulating ATR’s anti-apoptotic activity. It is well documented that PP2A is a heterotrimeric protein of various subunit isoforms, particularly the regulatory subunit B, each with distinct functions ( Janssens and Goris, 2001 ; Cho and Xu, 2007 ; Seshacharyulu et al, 2013 ; Sangodkar et al, 2016 ; Wlodarchak and Xing, 2016 ; Reynhout and Janssens, 2019 ). To achieve a specific inhibition of PP2A for its activity at ATR (Ser428) to reduce potential adverse side effects, identification of the regulatory subunit isoform specifically responsible for ATR (Ser428) dephosphorylation is necessary though it is out of scope of this study.…”