Pleiotrophin: A Cytokine with Diverse Functions and a Novel Signaling Pathway

doi:10.1006/abbi.2001.2705

Archives of Biochemistry and Biophysics

Volume 397, Issue 2, 15 January 2002, Pages 162-171

https://doi.org/10.1006/abbi.2001.2705 Get rights and content

Abstract

Pleiotrophin (PTN the protein, Ptn the gene) is a 136 amino acid secreted heparin-binding cytokine that signals diverse functions, including lineage-specific differentiation of glial progenitor cells, neurite outgrowth, and angiogenesis. Pleiotrophin gene expression is found in cells in early differentiation during different development periods and upregulated in cells with an early differentiation phenotype in wound repair. The Ptn gene is a protooncogene. It is strongly expressed in different human tumor cells and expression of the Ptn gene in tumor cells in vivo accelerates growth and stimulates tumor angiogenesis. Separate independent domains have been identified in PTN to signal transformation and tumor angiogenesis. Pleiotrophin is the first ligand of any of the known transmembrane tyrosine phosphatases. Pleiotrophin inactivates the receptor protein tyrosine phosphatase (RPTP) β/ζ. The interaction of PTN and RPTP β/ζ increases steady-state tyrosine phosphorylation of β-catenin. Pleiotrophin thus regulates both normal cell functions and different pathological conditions at many levels. It signals these functions through a transmembrane tyrosine phosphatase.

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Pleiotrophin: Analysis of the endothelialisation potential
2019, Advances in Medical Sciences
Endothelialisation of vascular substitutes, in fact, remains one of the most unsolved problems in cardiovascular diseases treatment. Stromal Derived Factor 1 (SDF-1) has been largely investigated as an endothelialisation promoter and Pleiotrophin is a promising alternative. Although it has been known to exert beneficial effects on different cell types, its potential as an inducer of proliferation and migration of endothelial cells was not investigated. Therefore, this work is aimed to compare the effects of Pleiotrophin on proliferation and migration of endothelial cells with respect to SDF-1.
Endothelial cell line EA.hy926 was treated with Pleiotrophin (50 ng/ml) or SDF-1 (50 ng/ml). Cell viability was evaluated by MTT assay and migration assays were performed in Transwell chambers. Wound healing potential was evaluated by scratch wound assay. CXCR4, RPTP β/ζ, PCNA and Rac1 expression was detected by Western Blot.
Interestingly, Pleiotrophin significantly increased the viability of the treated endothelial cells with respects to SDF-1. The migratory ability of the endothelial cells was also improved in the presence of Pleiotrophin with reference to the SDF-1 treatment. Moreover, Western Blot analysis showed how the treatment with Pleiotrophin can induce an increase in the expression of RPTP β/ζ, PCNA and Rac1 compared to SDF-1.
Due to the significant effects exerted on viability, migration and repair ability of endothelial cells compared to SDF-1, Pleiotrophin can be considered as an interesting molecule to promote re-endothelialisation.
Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA-induced dyskinesia
2018, Neuroscience Letters
Citation Excerpt :
PTN mediates several functions during development such as angiogenesis, mitogenesis, neuronal growth and differentiation. In the adult brain, its expression is restricted to some areas and has been reported to be upregulated after injury and plasticity [13]. Concerning the nigroestriatal system, PTN has been found to be neuroprotective for mesencephalic dopaminergic neurons in vitro [14] and in vivo [15].
L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats. We have also shown that both mRNA and protein levels of RPTPζ/β, a PTN receptor, were upregulated in the same experimental condition and expressed in striatal medium spiny neurons. The PTN-RPTPζ/β intracellular pathway has not been fully explored and it might be implicated in the striatal plastic changes triggered by L-DOPA treatment. RPTPζ/β is part of the postsynaptic density zone and modulates Fyn, a Src tyrosine kinase that regulates the NR2A and NR2B subunits of the NMDA receptor and has been singled out as a key molecule in the development of LID. In this study, we evaluated the changes in PTN and Fyn protein levels and Fyn phosphorylation status in the 6-OHDA rat model of PD rendered dyskinetic with L-DOPA. We found an increase in the number of PTN immunoreactive neurons, no changes in the amount of total Fyn but a significant increase in Fyn phosphorylation in the dorsolateral striatum of dyskinetic rats. Our results support the idea that both PTN and Fyn may be involved in the development of LID, further contributing to the understanding of its molecular mechanisms.
Development of inhibitors of receptor protein tyrosine phosphatase β/ζ (PTPRZ1) as candidates for CNS disorders
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
Both PTN and MK play important roles in development and repair of the central nervous system (CNS) [2]. The PTN and MK genes are widely expressed at different times in different cell types during development [3]. However, their expression levels are highly restricted to a few cell types in adults [4].
A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC₅₀ = 0,1 μM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity. Docking and molecular dynamics experiments have been used to analyze the binding mode and to explain the observed selectivity against PTP1B. An In vivo experiment has demonstrated that 10a can cross the BBB, thus promoting the possibility of moving forward these candidates for the development of drugs for the treatment of CNS disorders, such as drug addiction and neurodegenerative diseases.
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Prion diseases are fatal neurodegenerative disorders by which the native cellular prion protein (PrP^C) is misfolded into an accumulating, disease-associated isoform (PrP^D). To improve the understanding of prion pathogenesis and develop effective treatments, it is essential to elucidate factors contributing to cellular permissiveness. We previously isolated five clones from an immortalized subline of ovine microglia, two of which had demonstrated differential permissiveness to a natural isolate of sheep scrapie and distinct transcriptomic profiles. To more robustly identify factors contributing to this activity, relative permissiveness, cell proliferation, selected gene transcript level, and matrix metalloproteinase 2 (MMP2) activity were compared amongst all five clones. Differences in cell proliferation were not detected between clones; however, significant correlations were identified between relative permissiveness and genes associated with cell growth (i.e., RARRES1 and PTN), protein degradation (i.e., CTSB and SQSTM1), and heparin binding (i.e., SEPP1). MMP2 activity varied amongst clones, but did not correlate with permissiveness. These associations support the contribution of cell division and protein degradation on the permissiveness of cultured ovine microglia to PrP^D.
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^☆: This manuscript is dedicated to Earl R. Stadtman, Ph.D. As a mentor, Earl is without peer. As a friend and colleague, Earl is warm, supporting, loyal, and most valued. As a scientist and role model, he represents the highest standards of scientific integrity and research.

²: To whom correspondence and reprint requests should be addressed. Fax: (617) 632-0625. E-mail: [email protected].

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Pleiotrophin: A Cytokine with Diverse Functions and a Novel Signaling Pathway☆