LAR Receptor Tyrosine Phosphatase Family in Healthy and Diseased Brain

Abstract

Protein phosphatases are major regulators of signal transduction and they are involved in key cellular mechanisms such as proliferation, differentiation, and cell survival. Here we focus on one class of protein phosphatases, the type IIA Receptor-type Protein Tyrosine Phosphatases (RPTPs), or LAR-RPTP subfamily. In the last decade, LAR-RPTPs have been demonstrated to have great importance in neurobiology, from neurodevelopment to brain disorders. In vertebrates, the LAR-RPTP subfamily is composed of three members: PTPRF (LAR), PTPRD (PTPδ) and PTPRS (PTPσ), and all participate in several brain functions. In this review we describe the structure and proteolytic processing of the LAR-RPTP subfamily, their alternative splicing and enzymatic regulation. Also, we review the role of the LAR-RPTP subfamily in neural function such as dendrite and axon growth and guidance, synapse formation and differentiation, their participation in synaptic activity, and in brain development, discussing controversial findings and commenting on the most recent studies in the field. Finally, we discuss the clinical outcomes of LAR-RPTP mutations, which are associated with several brain disorders.

A disease model for Diffuse Intrinsic Pontine Glioma (DIPG) with mutations in TP53 and its application for drug repurposing

“…Nonfunctional PTPRD have been reported in other gliomas (Veeriah et al, 2009) and its loss was found to cause aberrant STAT3 activation promoting glioma (Ortiz et al, 2014). In adult brains PTPRD is involved in trans-synaptic interaction between neurons (Yoshida et al, 2011) and mediates cortical basal dendritic arborization, synaptic plasticity and neuronal growth in perineuronal nets (Carulli and Verhaagen, 2021; Cornejo et al, 2021).…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…Expression patterns for the three genes are distinct but certainly display overlap and the same can be said about their ligand and substrate specificity. A thorough review with a specific focus on their role in the brain was published recently ( Cornejo et al, 2021 ). A decade ago, only limited evidence linking these three RPTP genes to hereditary diseases had been gathered ( Hendriks and Pulido, 2013 ).…”

“…Having come to know PTPRD as a prime suspect for a plethora of disease conditions it is rather contrasting to see the limited hereditary dangers that have been tied to gene PTPRS , at least for the time being. Again largely thanks to studies in mutant mouse models the protein encoded by PTPRS , RPTPσ, demonstrated important roles in development and function of the nervous system ( Cornejo et al, 2021 ), including the control of synaptic transmission ( Brown et al, 2020 ). Also, RPTPσ functionality turned out to be a two-edged sword in the fight against intestinal inflammatory processes ( Ohtake et al, 2018 ); the protein not only protects the permeability of the epithelial layer ( Murchie et al, 2014 ) but also keeps dendritic cells under control ( Bunin et al, 2015 ).…”

The biological alterations of synapse/synapse formation in sepsis-associated encephalopathy

“…Synaptic adhesion molecules (SAMs) accumulate at pre-and postsynaptic sites, initiate synapse formation, and play an important role in regulating synaptic transmission and synaptic plasticity (Jang et al, 2017;Sudhof, 2018;Südhof, 2021;Yuzaki, 2018;Kim et al, 2021). The presynaptic SAMs are mostly present in excitatory and inhibitory synapses, like neurexins which are a family of SAMs involved in synapse formation and maturation, and leukocyte antigen-related (LAR)-type phosphotyrosine phosphatase receptors (PTPRs) (Sudhof, 2017;Cornejo et al, 2021;Fukai and Yoshida, 2021). In contrast, postsynaptic SAMs are more diverse as ligands for these presynaptic SAMs and are often specific for excitatory or inhibitory synapses.…”