The role of serine/threonine phosphatases in human development: Evidence from congenital disorders

Abstract

Reversible protein phosphorylation is a fundamental regulation mechanism in eukaryotic cell and organismal physiology, and in human health and disease. Until recently, and unlike protein kinases, mutations in serine/threonine protein phosphatases (PSP) had not been commonly associated with disorders of human development. Here, we have summarized the current knowledge on congenital diseases caused by mutations, inherited or de novo, in one of 38 human PSP genes, encoding a monomeric phosphatase or a catalytic subunit of a multimeric phosphatase. In addition, we highlight similar pathogenic mutations in genes encoding a specific regulatory subunit of a multimeric PSP. Overall, we describe 19 affected genes, and find that most pathogenic variants are loss-of-function, with just a few examples of gain-of-function alterations. Moreover, despite their widespread tissue expression, the large majority of congenital PSP disorders are characterised by brain-specific abnormalities, suggesting a generalized, major role for PSPs in brain development and function. However, even if the pathogenic mechanisms are relatively well understood for a small number of PSP disorders, this knowledge is still incomplete for most of them, and the further identification of downstream targets and effectors of the affected PSPs is eagerly awaited through studies in appropriate in vitro and in vivo disease models. Such lacking studies could elucidate the exact mechanisms through which these diseases act, and possibly open up new therapeutic avenues.

A retrospective analysis of phosphatase catalytic subunit gene variants in patients with rare disorders identifies novel candidate neurodevelopmental disease genes

“…Consequently, non-catalytic subunits may also represent a source of promising disease gene candidates. Indeed, nine genes encoding regulatory subunits of PP1 and PP2A are known to be associated with heritable disorders ( Vaneynde et al, 2022 ). However, systematic analysis of the non-catalytic subunits poses a challenge because of the large number of disparate proteins that interact with PPP catalytic subunits.…”

Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy

“…Red amino acids denote metal binding, while blue amino acids denote phosphate binding. The loop switch is indicated in orange [figure adapted from Vaneynde et al (2022 )]. (B) Structure of the catalytic PP2A Cα subunit.…”

A small molecule inhibitor of leucine carboxyl methyltransferase-1 inhibits cancer cell survival

“…In contrast to the kinases, there are approximately 200 known phosphatases, the majority of which are tyrosine phosphatases (Sacco et al, 2012). Of the two families of serine/threonine phosphatases, the protein phosphatase-2A family (PP2A) is known to regulate development, apoptosis, transcription, translation, growth and cell division (Moura and Conde, 2019;Vaneynde et al, 2022).…”

“…PP2A enzymes have a heterotrimeric structure consisting of scaffolding (A), catalytic (C) and regulatory (B) subunits. While there are two isoforms each of the A and C subunits, substrate specificity is mediated primarily by the 23 isoforms of the B subunits (Haesen et al, 2014;Vaneynde et al, 2022). PP2A heterotrimers containing the B55α (PR55α) regulatory subunit have been associated with oncogenic signaling (Smits et al, 1992;Hein et al, 2016;Di et al, 2017;Hein et al, 2019), and B55 subunits are found exclusively in forms of PP2A in which the carboxyl terminus of the catalytic subunit (PP2Ac) is methylated at leucine 309 (Longin et al, 2007).…”