Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Abstract

Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.

A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review

“…This variant can cause splice abnormalities and produce truncated proteins and thus might influence the binding function of the RVxF motif and PP1. To our knowledge, more than 50% of phosphoserine/threonine dephosphorylation reactions are catalyzed by PP1 in mammalian cells [ 25 ]. PP1 multifunctionally interacts with dozens of polypeptides that function as substrates, inhibitors, chaperones, anchoring/scaffolding proteins, and substrate-specifiers [ 24 , 26 ] and even those associated with heart physiology [ 27 ].…”

A Chinese Family with Noonan Syndrome Associated with a Heterozygous LZTR1 Mutation

“…This mutation can cause splice abnormalities and produce truncated proteins and thus may in uence the binding function of the RVxF motif and PP1. To our knowledge, more than 50% of phosphoserine/threonine dephosphorylation reactions are catalyzed by PP1 in mammalian cells [33] . PP1 multifunctionally interacts with dozens of polypeptides that function as substrates, inhibitors, chaperones, anchoring/scaffolding proteins, and substrate-speci ers [32.…”

Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

“…Our study implicates Pp1 as a key regulator of collective cohesion and migration in border cells. Pp1 catalytic subunits and their regulatory subunits are conserved across eukaryotes 30–32, 34 . The roles of specific Pp1 complexes in collective cell migration during development and in cancer have not been well studied.…”

“…These regulatory subunits form functional Pp1 complexes through binding to the Pp1 catalytic (Pp1c) subunits and mediate the recruitment of, or affinity for, particular substrates 31, 32 . Thus, despite the potential for pleiotropy, Pp1 complexes have specific and precise cellular functions in vivo , that range from regulation of protein synthesis, cell division and apoptosis to individual cell migration 33, 34 .…”