scholarly journals Structural basis for ligand-induced inactivation of protein tyrosine receptor type Z (PTPRZ): Physiological relevance of head-to-toe RPTP dimerization

2019 ◽  
Author(s):  
Akihiro Fujikawa ◽  
Hajime Sugawara ◽  
Naomi Tanga ◽  
Kentaro Ishii ◽  
Kazuya Kuboyama ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Competitive Inhibitor ◽  
Receptor Type ◽  
Structural Basis ◽  
Stoichiometric Ratio ◽  
Inhibitory Peptide ◽  
Dimer Formation ◽  
Protein Tyrosine ◽  
Extracellular Region

ABSTRACTProtein tyrosine phosphatase receptor type Z (PTPRZ) has two receptor isoforms (PTPRZ-A and -B) containing tandem PTP-D1 and -D2 domains intracellularly, with only D1 being active. Pleiotrophin (PTN) binding to the extracellular region of PTPRZ leads to the inactivation of PTPase, thereby inducing oligodendrocyte precursor cell (OPC) differentiation and myelination in the CNS. However, the mechanisms responsible for the ligand-induced inactivation of PTPRZ remain unclear. We herein revealed that the crystal structure of the intracellular region of PTPRZ (PTPRZ-ICR) showed the “head-to-toe”-type dimer conformation, with D2 masking the catalytic site of D1. Mass spectrometry (MS) revealed that PTPRZ-ICR proteins remained in monomer-dimer equilibrium in aqueous solution, and a substrate-derived inhibitory peptide or competitive inhibitor (SCB4380) specifically bound to the monomer form in a 1:1 stoichiometric ratio, supporting the “head-to-toe dimerization” model for inactivation. A D2 deletion (ΔD2) or dimer interface mutation (DDKK) disrupted dimer formation, while the binding of SCB4380 was maintained. Similar to wild-type PTPRZ-B, monomer-biased PTPRZ-B-ΔD2 and PTPRZ-B-DDKK mutants efficiently dephosphorylated p190RhoGAP at Tyr-1105 when co-expressed in BHK-21 cells. The catalytic activities of these mutants were not suppressed by a treatment with PTN, but were inhibited by the cell-permeable PTPase inhibitor NAZ2329. The PTN treatment did not enhance OPC differentiation in primary cultured glial cells prepared from ΔD2 or catalytically-inactive CS mutant knock-in mice. Our results indicate that PTN-induced PTPRZ inactivation is attained by dimer formation of the intracellular tandem PTP domains in the head-to-toe configuration, which is physiologically relevant to the control of OPC differentiation in vivo.

scholarly journals Structural Basis for Interactions Between Contactin Family Members and Protein-tyrosine Phosphatase Receptor Type G in Neural Tissues

2016 ◽  
Vol 291 (41) ◽  
pp. 21335-21349 ◽  
Author(s):  
Roman M. Nikolaienko ◽  
Michal Hammel ◽  
Véronique Dubreuil ◽  
Rana Zalmai ◽  
David R. Hall ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Family Members ◽  
Receptor Type ◽  
Structural Basis ◽  
Protein Tyrosine ◽  
Neural Tissues

scholarly journals N-Cadherin Is an In Vivo Substrate for Protein Tyrosine Phosphatase Sigma (PTPσ) and Participates in PTPσ-Mediated Inhibition of Axon Growth

2006 ◽  
Vol 27 (1) ◽  
pp. 208-219 ◽  
Author(s):  
Roberta Siu ◽  
Chris Fladd ◽  
Daniela Rotin
Keyword(s):  
Growth Rate ◽  
Protein Tyrosine Phosphatase ◽  
Knockout Mice ◽  
Tyrosine Phosphatase ◽  
Axon Growth ◽  
Differential Growth ◽  
Inhibitory Peptide ◽  
Protein Tyrosine ◽  
Protein Tyrosine Phosphatase Sigma

ABSTRACT Protein tyrosine phosphatase sigma (PTPσ) belongs to the LAR family of receptor tyrosine phosphatases and was previously shown to negatively regulate axon growth. The substrate for PTPσ and the effector(s) mediating this inhibitory effect were unknown. Here we report the identification of N-cadherin as an in vivo substrate for PTPσ. Using brain lysates from PTPσ knockout mice, in combination with substrate trapping, we identified a hyper-tyrosine-phosphorylated protein of ∼120 kDa in the knockout animals (relative to sibling controls), which was identified by mass spectrometry and immunoblotting as N-cadherin. β-Catenin also precipitated in the complex and was also a substrate for PTPσ. Dorsal root ganglion (DRG) neurons, which highly express endogenous N-cadherin and PTPσ, exhibited a faster growth rate in the knockout mice than in the sibling controls when grown on laminin or N-cadherin substrata. However, when N-cadherin function was disrupted by an inhibitory peptide or lowering calcium concentrations, the differential growth rate between the knockout and sibling control mice was greatly diminished. These results suggest that the elevated tyrosine phosphorylation of N-cadherin in the PTPσ−/− mice likely disrupted N-cadherin function, resulting in accelerated DRG nerve growth. We conclude that N-cadherin is a physiological substrate for PTPσ and that N-cadherin (and likely β-catenin) participates in PTPσ-mediated inhibition of axon growth.

scholarly journals Dimerization In Vivo and Inhibition of the Nonreceptor Form of Protein Tyrosine Phosphatase Epsilon

2003 ◽  
Vol 23 (15) ◽  
pp. 5460-5471 ◽  
Author(s):  
Hila Toledano-Katchalski ◽  
Zohar Tiran ◽  
Tal Sines ◽  
Gidi Shani ◽  
Shira Granot-Attas ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Direct Interaction ◽  
Receptor Type ◽  
Phosphatase Domain ◽  
Protein Tyrosine ◽  
Extracellular Domains ◽  
Type Protein

ABSTRACT cyt-PTPε is a naturally occurring nonreceptor form of the receptor-type protein tyrosine phosphatase (PTP) epsilon. As such, cyt-PTPε enables analysis of phosphatase regulation in the absence of extracellular domains, which participate in dimerization and inactivation of the receptor-type phosphatases receptor-type protein tyrosine phosphatase alpha (RPTPα) and CD45. Using immunoprecipitation and gel filtration, we show that cyt-PTPε forms dimers and higher-order associations in vivo, the first such demonstration among nonreceptor phosphatases. Although cyt-PTPε readily dimerizes in the absence of exogenous stabilization, dimerization is increased by oxidative stress. Epidermal growth factor receptor stimulation can affect cyt-PTPε dimerization and tyrosine phosphorylation in either direction, suggesting that cell surface receptors can relay extracellular signals to cyt-PTPε, which lacks extracellular domains of its own. The inactive, membrane-distal (D2) phosphatase domain of cyt-PTPε is a major contributor to intermolecular binding and strongly interacts in a homotypic manner; the presence of D2 and the interactions that it mediates inhibit cyt-PTPε activity. Intermolecular binding is inhibited by the extreme C and N termini of D2. cyt-PTPε lacking these regions constitutively dimerizes, and its activities in vitro towards para-nitrophenylphosphate and in vivo towards the Kv2.1 potassium channel are markedly reduced. We conclude that physiological signals can regulate dimerization and phosphorylation of cyt-PTPε in the absence of direct interaction between the PTP and extracellular molecules. Furthermore, dimerization can be mediated by the D2 domain and does not strictly require the presence of PTP extracellular domains.

scholarly journals Protein tyrosine phosphatase receptor type C (PTPRC or CD45)

2021 ◽  
pp. jclinpath-2020-206927
Author(s):  
Maryam Ahmed Al Barashdi ◽  
Ahlam Ali ◽  
Mary Frances McMullin ◽  
Ken Mills
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Biological Activities ◽  
Tyrosine Phosphatase ◽  
Cell Types ◽  
Receptor Type ◽  
Future Research ◽  
Protein Tyrosine ◽  
Type C ◽  
Almost All

The leucocyte common antigen, protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45, is a transmembrane glycoprotein, expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation. Disruption of the equilibrium between protein tyrosine kinase and phosphatase activity (from CD45 and others) can result in immunodeficiency, autoimmunity, or malignancy. CD45 is normally present on the cell surface, therefore it works upstream of a large signalling network which differs between cell types, and thus the effects of CD45 on these cells are also different. However, it is becoming clear that CD45 plays an essential role in the innate immune system and this is likely to be a key area for future research. In this review of PTPRC (CD45), its structure and biological activities as well as abnormal expression of CD45 in leukaemia and lymphoma will be discussed.

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