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.

Keywords: PTPdelta; PTPsigma; brain disorders; protein phosphatase; receptor protein tyrosine phosphatase (RPTP).

FIGURE 1

LAR-RPTPs protein structure and alternative splicing sites. The structure of all three receptors consists of an extracellular portion of three Ig-like domains and eight extracellular fibronectin type III domains, a transmembrane region, and two intracellular protein tyrosine phosphatase domains: a membrane proximal catalytically active domain and a membrane distal domain with no phosphatase activity. Alternative splicing sites are marked as mini-exons meA-D, and the aminoacidic sequences of meA3, meA6 and meB are shown. Ig: Ig-like domains; FN: fibronectin type III domains; D1 and D2: phosphatase domains.

FIGURE 2

LAR-RPTPs proteolytic processing. After its translation, LAR-RPTPs are processed in the trans-Golgi by furin-like endoproteases (FLE) (1), to later be translocated to the cell surface, where they will be integrated into the membrane as a complex of two subunits; the extracellular E-subunit and the intracellular P-subunit, who remain non-covalently bound. Extracellularly, α-secretase can also induce a cleavage in the ectodomain of the P-subunit (2), which releases the extracellular portion of LAR-RPTPs. Also, intracellular tandem phosphatase domains are proteolytically processed by γ-secretase (3), inducing LAR-RPTPs catalytic region internalization and its proteasomal degradation (4).

FIGURE 3

PTPRS signaling modulates dendrite and axon growth. (A) PTPRS interaction with CSPGs promotes TrkB dephosphorylation which reduces dendrite growth in a mechanism that appears to be mediated by PTPRS-NME2 interaction (Kurihara and Yamashita, 2012; Lesnikova et al., 2020). (B) PTPRS-HSPGs interaction induce PTPRS dimer formation, which inactivates its catalytic activity and favors axon growth; while the interaction with CSPGs promotes the PTPRS monomer conformation, inducing its catalytic activity and inhibits axonal growth (Shen et al., 2009; Coles et al., 2011). (C) PTPRS interaction with N-cadherin dephosphorylates N-cadherin and β-catenin, which favors N-cadherin-β-catenin interaction, stabilizes actin cytoskeleton, and reduces axonal growth (Siu et al., 2007).

FIGURE 4

LAR-RPTPs trans-synaptic interactions induce synaptic differentiation. Summary of LAR-RPTPs and their synaptic partners whose interactions induce excitatory or inhibitory synapse differentiation. LAR-RPTPs interactions that induce differentiation unidirectionally are represented with dashed lines, while interactions inducing bidirectional differentiation are represented with solid lines.

FIGURE 5

PTPRD absence induce aberrant embryonic cortical neurogenesis. (A) PTPRD dephosphorylates PDGFRβ and TrkB receptor tyrosine kinases to control their activity, and the activation of MEK/ERK intracellular signaling. (B) This induces the normal Tbr2-positive intermediate progenitor cells proliferation and neurogenesis, and the correct localization of Satb2 and Tbr1-positive neurons into the brain cortex. However (C) when PTPRD expression is lost, NPCs have increased phosphorylation of PDGFRβ and TrkB, which derives in the hyperactivation of the MEK/ERK intracellular signaling. (D) This induces an increase in Tbr2-positive intermediate progenitor cell proliferation, and consequently, aberrant increased neurogenesis and impaired positioning of Satb2 and Tbr1-positive neurons into the brain cortex.

FIGURE 6

LAR-RPTPs participate in several neural functions. All three LAR-RPTPs are implicated in various functions involved in the biology of neurons, such as neurite and axon growth, axon guidance, synaptic formation and differentiation, synaptic functions, and brain development.