The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Thomas F Deuel - One of the best experts on this subject based on the ideXlab platform.
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the neurotrophic factor Pleiotrophin modulates amphetamine seeking behaviour and amphetamine induced neurotoxic effects evidence from Pleiotrophin knockout mice
Addiction Biology, 2010Co-Authors: Esther Gramage, Thomas F Deuel, Pablo Perezpinera, Laura Ezquerra, Alessia Putelli, Maria Jose Polanco, Carmen Gonzalezmartin, Luis F Alguacil, Gonzalo HerradonAbstract:Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN ―/―) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN ―/―) and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN ―/― mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN ―/― mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly we found in concomitant in vitro studies that PTN (3 μM) limits amphetamine (1 mM)-induced loss of viability of PC 12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.
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Pleiotrophin a multifunctional angiogenic factor mechanisms and pathways in normal and pathological angiogenesis
Current Opinion in Hematology, 2008Co-Authors: Pablo Perezpinera, James R Berenson, Thomas F DeuelAbstract:Purpose of reviewThis study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine Pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis.Recent findingsPleiotrophin is directly angiogenic; it i
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Pleiotrophin a multifunctional tumor promoter through induction of tumor angiogenesis remodeling of the tumor microenvironment and activation of stromal fibroblasts
Cell Cycle, 2007Co-Authors: Pablo Perezpinera, Yunchao Chang, Thomas F DeuelAbstract:Pleiotrophin (PTN, Ptn) is a widely expressed, developmentally regulated 136 amino acid secreted heparin-binding cytokine. It signals through a unique signaling pathway; the PTN receptor is the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta. RPTPbeta/zeta is inactivated by PTN, which leads to increased tyrosine phosphorylation of the downstream targets of the PTN/RPTPbeta/zeta signaling pathway. Pleiotrophin gene expression is found in cells in early differentiation during different developmental periods. It is upregulated in cells with an early differentiation phenotype in wound repair. The Ptn gene also is a proto-oncogene; PTN is expressed in human tumor cells, and, in cell lines derived from human tumors that express Ptn, Ptn expression is constitutive and thus "inappropriate". Importantly, properties of different cells induced by PTN in PTN-stimulated cells are strikingly similar to properties of highly malignant cells. Furthermore, transformed cells into which Ptn is introduced undergo "switches" to malignant cells of higher malignancy with properties that are strikingly similar to properties of PTN-stimulated cells. These unique features of PTN support the conclusion that constitutive PTN signaling in malignant cells that inappropriately express Ptn functions as a potent tumor promoter. Recently, in confirmation, Ptn targeted by the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model was found to promote breast cancers to a more aggressive breast cancer cell phenotype that morphologically closely resembles scirrhous carcinoma in human; in addition, it promoted a striking increase in tumor angiogenesis and a remarkable degree of remodeling of the micro-environment. Pleiotrophin thus regulates both different normal and pathological functions; collectively, the different studies have uncovered the unique ability of a single cytokine PTN, which signals through the unique PTN/RPTPbeta/zeta signaling pathway, to induce the many properties associated with tumor promotion in the malignant cells that constitutively express Ptn and in their microenvironment.
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dominant negative Pleiotrophin induces tetraploidy and aneuploidy in u87mg human glioblastoma cells
Biochemical and Biophysical Research Communications, 2006Co-Authors: Yunchao Chang, James R Berenson, Zhaoyi Wang, Thomas F DeuelAbstract:Pleiotrophin (PTN, Ptn) is an 18kDa secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant-negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant-negative PTN (U87MG/PTN1-40 cells); here, we report that the dominant-negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells.
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Pleiotrophin induces formation of functional neovasculature in vivo
Biochemical and Biophysical Research Communications, 2005Co-Authors: Karen L Christman, Gonzalo Herradon, Qizhi Fang, Anne J Kim, Richard E Sievers, Hubert H Fok, Albert F Candia, Kenneth J Colley, Laura Ezquerra, Thomas F DeuelAbstract:Abstract Pleiotrophin (PTN) is a heparin-binding growth/differentiation inducing cytokine that shares 50% amino acid sequence identity and striking domain homology with Midkine (MK), the only other member of the Ptn / Mk developmental gene family. The Ptn gene is expressed in sites of early vascular development in embryos and in healing wounds and its constitutive expression in many human tumors is associated with an angiogenic phenotype, suggesting that PTN has an important role in angiogenesis during development and in wound repair and advanced malignancies. To directly test whether PTN is angiogenic in vivo, we injected a plasmid to express PTN into ischemic myocardium in rats. Pleiotrophin stimulated statistically significant increases in both normal appearing new capillaries and arterioles each of which had readily detectable levels of the arteriole marker, smooth muscle cell α-actin. Furthermore, the newly formed blood vessels were shown to interconnect with the existent coronary vascular system. The results of these studies demonstrate directly that PTN is an effective angiogenic agent in vivo able to initiate new vessel formation that is both normal in appearance and function. The data suggest that PTN signals the more “complete” new blood vessel formation through its ability to stimulate different functions in different cell types not limited to the endothelial cell.
Anton Wellstein - One of the best experts on this subject based on the ideXlab platform.
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midkine and Pleiotrophin concentrations in needle biopsies of breast and lung masses
Criminal Behaviour and Mental Health, 2017Co-Authors: Nicole Michelle Giamanco, Anton Wellstein, Youn Hee Jee, Craig D Shriver, Thomas A Summers, Jeffrey BaronAbstract:Background/objective Midkine (MDK) and Pleiotrophin (PTN) are two closely related heparin-binding growth factors which are overexpressed in a wide variety of human cancers. We hypothesized that the concentrations of these factors in washout of biopsy needles would be higher in breast and lung cancer than in benign lesions. Methods Seventy subjects underwent pre-operative core needle biopsies of 78 breast masses (16 malignancies). In 11 subjects, fine needle aspiration was performed ex vivo on 7 non-small cell lung cancers and 11 normal lung specimens within surgically excised lung tissue. The biopsy needle was washed with buffer for immunoassay. Results The MDK/DNA and the PTN/DNA ratio in most of the malignant breast masses were similar to the ratios in benign masses except one lobular carcinoma in situ (24-fold higher PTN/DNA ratio than the average benign mass). The MDK/DNA and PTN/DNA ratio were similar in most malignant and normal lung tissue except one squamous cell carcinoma (38-fold higher MDK/DNA ratio than the average of normal lung tissue). Conclusions Both MDK and PTN are readily measurable in washout of needle biopsy samples from breast and lung masses and levels are highly elevated only in a specific subset of these malignancies.
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midkine and Pleiotrophin concentrations in amniotic fluid in healthy and complicated pregnancies
PLOS ONE, 2016Co-Authors: Youn Hee Jee, Anton Wellstein, Yael Lebenthal, Piya Chaemsaithong, Gai Yan, Ivana Peran, Roberto Romero, Jeffrey BaronAbstract:Background Midkine (MDK) and Pleiotrophin (PTN) are heparin-binding growth factors that, in rodents, are highly expressed in early life and decrease to undetectable levels by adulthood. The potential roles of MDK and PTN in human growth and development are not completely elucidated. Method and Findings To delineate the role of MDK and PTN in human development, we developed high sensitivity assays to measure their concentrations in amniotic fluid (AF) at various gestational ages in both healthy and complicated pregnancies. We found that both of these growth factors could be readily measured in AF and that the concentrations were higher than most cytokines previously reported in AF. Conclusion The concentration of MDK but not that of PTN declined with gestational age. Both MDK and PTN concentrations were found to be lower in pregnancies that were complicated by chorioamnionitis at term, raising the possibility that these growth factors might be useful as markers for infection.
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increased Pleiotrophin concentrations in papillary thyroid cancer
PLOS ONE, 2016Co-Authors: Youn Hee Jee, Anton Wellstein, Samira M Sadowski, Francesco S Celi, Mark Raffeld, David B Sacks, Alan T Remaley, Electron Kebebew, Jeffrey BaronAbstract:Background Thyroid nodules are common, and approximately 5% of these nodules are malignant. Pleiotrophin (PTN) is a heparin-binding growth factor which is overexpressed in many cancers. The expression of PTN in papillary thyroid cancer (PTC) is unknown.
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midkine and Pleiotrophin concentrations in biopsy needle washout of breast masses
Journal of Clinical Oncology, 2014Co-Authors: Nicole Michelle Giamanco, Anton Wellstein, Youn Hee Jee, Craig D Shriver, Thomas A Summers, Jeffrey BaronAbstract:e22104 Background: The primary preoperative diagnostic method for distinguishing malignant from benign breast masses is core biopsy histology, but this approach can be inconclusive. Midkine (MDK) a...
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anti apoptotic signaling of Pleiotrophin through its receptor anaplastic lymphoma kinase
Journal of Biological Chemistry, 2002Co-Authors: Emma T Bowden, Gerald E Stoica, Anton WellsteinAbstract:The secreted growth factor Pleiotrophin (PTN) can induce mitogenesis in cells that express the receptor for this growth factor, anaplastic lymphoma kinase (ALK). Here we examine the ability of PTN to produce anti-apoptotic signals. We demonstrate that PTN is a survival factor for SW-13 epithelial cells and show that ribozyme-mediated depletion of ALK from SW-13 cells abolishes this effect of PTN. Furthermore, in serum-starved NIH3T3 fibroblasts PTN prevents apoptosis (measured by annexin V staining) with an EC(50) of 0.2 ng/ml and induces cell growth at higher concentrations of PTN. A polyclonal antibody against the PTN ligand-binding domain of the ALK receptor (alpha-LBD) was a partial agonist for ALK in NIH3T3 cells. This alpha-LBD antibody showed high agonist activity for anti-apoptosis (56 +/- 9% relative to PTN), low agonist activity for cell growth (21 +/- 1% relative to PTN), and was an antagonist of PTN-induced cell growth (61 +/- 2% inhibition). Both MAP kinase and phosphatidylinositol (PI) 3-kinase cascades in NIH3T3 cells were activated by PTN, and this effect persisted for up to 3 h. Surprisingly, the anti-apoptotic effect of PTN was completely blocked by the MAP kinase inhibitor UO126, but was not affected by the PI 3-kinase inhibitor LY294002. In contrast, PTN-dependent cell growth required both MAPK and PI 3-kinase activity. We conclude that anti-apoptotic signaling of PTN through ALK in NIH3T3 fibroblasts is via the MAP kinase pathway.
Masaharu Noda - One of the best experts on this subject based on the ideXlab platform.
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a receptor like protein tyrosine phosphatase ptpζ rptpβ binds a heparin binding growth factor midkine involvement of arginine 78 of midkine in the high affinity binding to ptpζ
Journal of Biological Chemistry, 1999Co-Authors: Nobuaki Maeda, Kenji Kadomatsu, Takashi Muramatsu, Keiko Ichiharatanaka, Terutoshi Kimura, Masaharu NodaAbstract:Abstract Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to Pleiotrophin. Pleiotrophin has been demonstrated to bind to protein-tyrosine phosphatase ζ (PTPζ) with high affinity. In this study, we examined the binding of midkine to PTPζ by solid-phase binding assay. Midkine and Pleiotrophin binding to PTPζ were equally inhibited by soluble Pleiotrophin and also by some specific glycosaminoglycans. For both bindings, Scatchard analysis revealed low (3.0 nm) and high (0.58 nm) affinity binding sites. These results suggested that PTPζ is a common receptor for midkine and Pleiotrophin. Midkine is structurally divided into the N- and C-terminal halves, and the latter exhibited full activity for PTPζ binding and neuronal migration induction. The C-terminal half contains two heparin-binding sites consisting of clusters of basic amino acids, Clusters I and II. A mutation at Arg78 in Cluster I resulted in loss of the high affinity binding and reduced neuronal migration-inducing activity, while mutations at Lys83 and Lys84 in Cluster II showed almost no effect on either activity. Chondroitinase ABC-treated PTPζ exhibited similar low affinity binding both to the native midkine and midkine mutants at Arg78. These results suggested that Arg78 in midkine plays an essential role in high affinity binding to PTPζ by interacting with the chondroitin sulfate portion of this receptor.
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involvement of receptor like protein tyrosine phosphatase ζ rptpβ and its ligand Pleiotrophin heparin binding growth associated molecule hb gam in neuronal migration
Journal of Cell Biology, 1998Co-Authors: Nobuaki Maeda, Masaharu NodaAbstract:Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase ζ (PTPζ)/receptor-like protein tyrosine phosphatase β (RPTPβ) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPζ isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of Pleiotrophin-PTPζ interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-l-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-l-lysine–induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPζ, PTPζ-S, an extracellular secreted form of PTPζ, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the Pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited Pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the Pleiotrophin-binding site of PTPζ, and PTPζ-Pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPζ are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPζ is involved in the neuronal migration as a neuronal receptor of Pleiotrophin distributed along radial glial fibers.
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6b4 proteoglycan phosphacan an extracellular variant of receptor like protein tyrosine phosphatase ζ rptpβ binds Pleiotrophin heparin binding growth associated molecule hb gam
Journal of Biological Chemistry, 1996Co-Authors: Nobuaki Maeda, Taeko Nishiwaki, Takafumi Shintani, Hiroki Hamanaka, Masaharu NodaAbstract:Abstract A major chondroitin sulfate proteoglycan in the brain, 6B4 proteoglycan/phosphacan, corresponds to the extracellular region of a receptor-like protein-tyrosine phosphatase, PTPζ/RPTPβ. Here, we purified and characterized 6B4 proteoglycan-binding proteins from rat brain. From the CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid) extract of brain microsomal fractions, 18-, 28-, and 40-kDa proteins were specifically isolated using 6B4 proteoglycan-Sepharose. N-terminal amino acid sequencing identified the 18-kDa protein as Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM). Scatchard analysis of 6B4 proteoglycan-Pleiotrophin binding revealed low (Kd = 3 n) and high (Kd = 0.25 n) affinity binding sites. Chondroitinase ABC digestion of the proteoglycan decreased the binding affinities to a single value (Kd = 13 n) without changing the number of binding sites. This suggested the presence of two subpopulations of the proteoglycan with different chondroitin sulfate structures. Heparin potently inhibited binding of 6B4 proteoglycan to Pleiotrophin (IC50 = 3.5 ng/ml). Heparan sulfate and chondroitin sulfate C inhibited moderately (IC50 = 150 and 400 ng/ml, respectively), but, in contrast, chondroitin sulfate A and keratan sulfate were poor inhibitors (IC50 > 100 μg/ml). Immunofluorescence and immunoblotting analyses indicated that both 6B4 proteoglycan and PTPζ are located on cortical neurons. Anti-6B4 proteoglycan antibody added to the culture medium suppressed Pleiotrophin-induced neurite outgrowth of cortical neurons. These results suggested that interaction between 6B4 proteoglycan and Pleiotrophin is required for the action of Pleiotrophin, and chondroitin sulfate chains on 6B4 proteoglycan play regulatory roles in its binding.
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6b4 proteoglycan phosphacan an extracellular variant of receptor like protein tyrosine phosphatase ζ rptpβ binds Pleiotrophin heparin binding growth associated molecule hb gam
Journal of Biological Chemistry, 1996Co-Authors: Nobuaki Maeda, Taeko Nishiwaki, Takafumi Shintani, Hiroki Hamanaka, Masaharu NodaAbstract:A major chondroitin sulfate proteoglycan in the brain, 6B4 proteoglycan/phosphacan, corresponds to the extracellular region of a receptor-like protein-tyrosine phosphatase, PTPzeta/RPTPbeta. Here, we purified and characterized 6B4 proteoglycan-binding proteins from rat brain. From the CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid) extract of brain microsomal fractions, 18-, 28-, and 40-kDa proteins were specifically isolated using 6B4 proteoglycan-Sepharose. N-terminal amino acid sequencing identified the 18-kDa protein as Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM). Scatchard analysis of 6B4 proteoglycan-Pleiotrophin binding revealed low (Kd = 3 nM) and high (Kd = 0.25 nM) affinity binding sites. Chondroitinase ABC digestion of the proteoglycan decreased the binding affinities to a single value (Kd = 13 nM) without changing the number of binding sites. This suggested the presence of two subpopulations of the proteoglycan with different chondroitin sulfate structures. Heparin potently inhibited binding of 6B4 proteoglycan to Pleiotrophin (IC50 = 3.5 ng/ml). Heparan sulfate and chondroitin sulfate C inhibited moderately (IC50 = 150 and 400 ng/ml, respectively), but, in contrast, chondroitin sulfate A and keratan sulfate were poor inhibitors (IC50 > 100 microg/ml). Immunofluorescence and immunoblotting analyses indicated that both 6B4 proteoglycan and PTPzeta are located on cortical neurons. Anti-6B4 proteoglycan antibody added to the culture medium suppressed Pleiotrophin-induced neurite outgrowth of cortical neurons. These results suggested that interaction between 6B4 proteoglycan and Pleiotrophin is required for the action of Pleiotrophin, and chondroitin sulfate chains on 6B4 proteoglycan play regulatory roles in its binding.
Nobuaki Maeda - One of the best experts on this subject based on the ideXlab platform.
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heterogeneity of the chondroitin sulfate portion of phosphacan 6b4 proteoglycan regulates its binding affinity for Pleiotrophin heparin binding growth associated molecule
Journal of Biological Chemistry, 2003Co-Authors: Nobuaki Maeda, Kazuyuki Sugahara, Yuki Yajima, Tadahisa Mikami, Tomio YabeAbstract:Abstract PTPζ is a receptor-type protein-tyrosine phosphatase that is synthesized as a chondroitin sulfate proteoglycan and uses Pleiotrophin as a ligand. The chondroitin sulfate portion of this receptor is essential for high affinity binding to Pleiotrophin. Here, we purified phosphacan, which corresponds to the extracellular domain of PTPζ, from postnatal day 7 (P7) and P12 rat cerebral cortex (PG-P7 and PG-P12, respectively) and from P20 rat whole brain (PG-P20). The chondroitin sulfate of these preparations displayed immunologically and compositionally different structures. In particular, only PG-P20 reacted with the monoclonal antibody MO-225, which recognizes chondroitin sulfate containing the GlcA(2S)β1–3GalNAc(6S) disaccharide unit (D unit). Analysis of the chondroitinase digestion products revealed that GlcAβ1–3GalNAc(4S) disaccharide unit (A unit) was the major component in these preparations and that PG-P20 contained 1.3% D unit, which was not detected in PG-P7 and PG-P12. Interaction analysis using a surface plasmon resonance biosensor indicated that PG-P20 had ∼5-fold stronger affinity for Pleiotrophin (dissociation constant (KD) = 0.14 nm) than PG-P7 and PG-P12, although all these preparations showed similar low affinity binding to Pleiotrophin after chondroitinase ABC digestion (KD = 1.4 ∼ 1.6 nm). We also found that shark cartilage chondroitin sulfate D containing ∼20% D unit bound to Pleiotrophin with moderate affinity (KD = 2.7 nm), whereas whale cartilage chondroitin sulfate A showed no binding to this growth factor. These results suggest that variation of chondroitin sulfate plays important roles in the regulation of signal transduction in the brain.
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heterogeneity of the chondroitin sulfate portion of phosphacan 6b4 proteoglycan regulates its binding affinity for Pleiotrophin heparin binding growth associated molecule
Journal of Biological Chemistry, 2003Co-Authors: Nobuaki Maeda, Kazuyuki Sugahara, Yuki Yajima, Tadahisa Mikami, Tomio YabeAbstract:PTP zeta is a receptor-type protein-tyrosine phosphatase that is synthesized as a chondroitin sulfate proteoglycan and uses Pleiotrophin as a ligand. The chondroitin sulfate portion of this receptor is essential for high affinity binding to Pleiotrophin. Here, we purified phosphacan, which corresponds to the extracellular domain of PTP zeta, from postnatal day 7 (P7) and P12 rat cerebral cortex (PG-P7 and PG-P12, respectively) and from P20 rat whole brain (PG-P20). The chondroitin sulfate of these preparations displayed immunologically and compositionally different structures. In particular, only PG-P20 reacted with the monoclonal antibody MO-225, which recognizes chondroitin sulfate containing the GlcA(2S)beta 1-3GalNAc(6S) disaccharide unit (D unit). Analysis of the chondroitinase digestion products revealed that GlcA beta 1-3GalNAc(4S) disaccharide unit (A unit) was the major component in these preparations and that PG-P20 contained 1.3% D unit, which was not detected in PG-P7 and PG-P12. Interaction analysis using a surface plasmon resonance biosensor indicated that PG-P20 had approximately 5-fold stronger affinity for Pleiotrophin (dissociation constant (KD) = 0.14 nM) than PG-P7 and PG-P12, although all these preparations showed similar low affinity binding to Pleiotrophin after chondroitinase ABC digestion (KD = 1.4 approximately 1.6 nM). We also found that shark cartilage chondroitin sulfate D containing approximately 20% D unit bound to Pleiotrophin with moderate affinity (KD = 2.7 nM), whereas whale cartilage chondroitin sulfate A showed no binding to this growth factor. These results suggest that variation of chondroitin sulfate plays important roles in the regulation of signal transduction in the brain.
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a receptor like protein tyrosine phosphatase ptpζ rptpβ binds a heparin binding growth factor midkine involvement of arginine 78 of midkine in the high affinity binding to ptpζ
Journal of Biological Chemistry, 1999Co-Authors: Nobuaki Maeda, Kenji Kadomatsu, Takashi Muramatsu, Keiko Ichiharatanaka, Terutoshi Kimura, Masaharu NodaAbstract:Abstract Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to Pleiotrophin. Pleiotrophin has been demonstrated to bind to protein-tyrosine phosphatase ζ (PTPζ) with high affinity. In this study, we examined the binding of midkine to PTPζ by solid-phase binding assay. Midkine and Pleiotrophin binding to PTPζ were equally inhibited by soluble Pleiotrophin and also by some specific glycosaminoglycans. For both bindings, Scatchard analysis revealed low (3.0 nm) and high (0.58 nm) affinity binding sites. These results suggested that PTPζ is a common receptor for midkine and Pleiotrophin. Midkine is structurally divided into the N- and C-terminal halves, and the latter exhibited full activity for PTPζ binding and neuronal migration induction. The C-terminal half contains two heparin-binding sites consisting of clusters of basic amino acids, Clusters I and II. A mutation at Arg78 in Cluster I resulted in loss of the high affinity binding and reduced neuronal migration-inducing activity, while mutations at Lys83 and Lys84 in Cluster II showed almost no effect on either activity. Chondroitinase ABC-treated PTPζ exhibited similar low affinity binding both to the native midkine and midkine mutants at Arg78. These results suggested that Arg78 in midkine plays an essential role in high affinity binding to PTPζ by interacting with the chondroitin sulfate portion of this receptor.
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involvement of receptor like protein tyrosine phosphatase ζ rptpβ and its ligand Pleiotrophin heparin binding growth associated molecule hb gam in neuronal migration
Journal of Cell Biology, 1998Co-Authors: Nobuaki Maeda, Masaharu NodaAbstract:Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase ζ (PTPζ)/receptor-like protein tyrosine phosphatase β (RPTPβ) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPζ isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of Pleiotrophin-PTPζ interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-l-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-l-lysine–induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPζ, PTPζ-S, an extracellular secreted form of PTPζ, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the Pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited Pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the Pleiotrophin-binding site of PTPζ, and PTPζ-Pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPζ are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPζ is involved in the neuronal migration as a neuronal receptor of Pleiotrophin distributed along radial glial fibers.
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6b4 proteoglycan phosphacan an extracellular variant of receptor like protein tyrosine phosphatase ζ rptpβ binds Pleiotrophin heparin binding growth associated molecule hb gam
Journal of Biological Chemistry, 1996Co-Authors: Nobuaki Maeda, Taeko Nishiwaki, Takafumi Shintani, Hiroki Hamanaka, Masaharu NodaAbstract:Abstract A major chondroitin sulfate proteoglycan in the brain, 6B4 proteoglycan/phosphacan, corresponds to the extracellular region of a receptor-like protein-tyrosine phosphatase, PTPζ/RPTPβ. Here, we purified and characterized 6B4 proteoglycan-binding proteins from rat brain. From the CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid) extract of brain microsomal fractions, 18-, 28-, and 40-kDa proteins were specifically isolated using 6B4 proteoglycan-Sepharose. N-terminal amino acid sequencing identified the 18-kDa protein as Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM). Scatchard analysis of 6B4 proteoglycan-Pleiotrophin binding revealed low (Kd = 3 n) and high (Kd = 0.25 n) affinity binding sites. Chondroitinase ABC digestion of the proteoglycan decreased the binding affinities to a single value (Kd = 13 n) without changing the number of binding sites. This suggested the presence of two subpopulations of the proteoglycan with different chondroitin sulfate structures. Heparin potently inhibited binding of 6B4 proteoglycan to Pleiotrophin (IC50 = 3.5 ng/ml). Heparan sulfate and chondroitin sulfate C inhibited moderately (IC50 = 150 and 400 ng/ml, respectively), but, in contrast, chondroitin sulfate A and keratan sulfate were poor inhibitors (IC50 > 100 μg/ml). Immunofluorescence and immunoblotting analyses indicated that both 6B4 proteoglycan and PTPζ are located on cortical neurons. Anti-6B4 proteoglycan antibody added to the culture medium suppressed Pleiotrophin-induced neurite outgrowth of cortical neurons. These results suggested that interaction between 6B4 proteoglycan and Pleiotrophin is required for the action of Pleiotrophin, and chondroitin sulfate chains on 6B4 proteoglycan play regulatory roles in its binding.
Evangelia Papadimitriou - One of the best experts on this subject based on the ideXlab platform.
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Pleiotrophin and its receptor protein tyrosine phosphatase beta zeta as regulators of angiogenesis and cancer
Biochimica et Biophysica Acta, 2016Co-Authors: Evangelia Papadimitriou, Evangelia Pantazaka, Penelope Castana, Thomas Tsalios, Alexandros Polyzos, Dimitris BeisAbstract:Pleiotrophin (PTN) is a secreted heparin-binding growth factor that through its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) has a significant regulatory effect on angiogenesis and cancer. PTN and RPTPβ/ζ are over-expressed in several types of human cancers and regulate important cancer cell functions in vitro and cancer growth in vivo. This review begins with a brief introduction of PTN and the regulation of its expression. PTN receptors are described with special emphasis on RPTPβ/ζ, which also interacts with and/or affects the function of other important targets for cancer therapy, such as vascular endothelial growth factor A, ανβ3 and cell surface nucleolin. PTN biological activities related to angiogenesis and cancer are extensively discussed. Finally, up to date approaches of targeting PTN or RPTPβ/ζ for cancer treatment are presented. Insights into the regulatory role of PTN/RPTPβ/ζ on angiogenesis will be extremely beneficial for future development of alternative anti-angiogenic approaches in cancer therapy.
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the role of Pleiotrophin in bone repair
Injury-international Journal of The Care of The Injured, 2014Co-Authors: Margarita Lamprou, Angelos Kaspiris, Elias Panagiotopoulos, Peter V Giannoudis, Evangelia PapadimitriouAbstract:Bone has an enormous capacity for growth, regeneration, and remodelling, largely due to induction of osteoblasts that are recruited to the site of bone formation. Although the pathways involved have not been fully elucidated, it is well accepted that the immediate environment of the cells is likely to play a role via cell–matrix interactions, mediated by several growth factors. Formation of new blood vessels is also significant and interdependent to bone formation, suggesting that enhancement of angiogenesis could be beneficial during the process of bone repair. Pleiotrophin (PTN), also called osteoblast-specific factor 1, is a heparin-binding angiogenic growth factor, with a well-defined and significant role in both physiological and pathological angiogenesis. In this review we summarise the existing evidence on the role of PTN in bone repair.
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roles of Pleiotrophin in tumor growth and angiogenesis
European Cytokine Network, 2009Co-Authors: Evangelia Papadimitriou, Constantinos M Mikelis, Evgenia Lampropoulou, Marina Koutsioumpa, Katerina Theochari, Sotiria Tsirmoula, Christina Theodoropoulou, Margarita Lamprou, Evanthia Sfaelou, Dionyssios VourtsisAbstract:Pleiotrophin (PTN) is a heparin-binding growth factor with diverse biological activities, the most studied of these being those related to the nervous system, tumor growth and angiogenesis. Although interest in the involvement of PTN in tumor growth is increasing, many questions remain unanswered, particularly concerning the receptors and the signaling pathways involved. In this review, we briefly introduce PTN, and summarize data on its involvement in tumor growth and angiogenesis, and on what is known to date concerning the receptors and pathways involved.
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integrin alpha v beta 3 is a Pleiotrophin receptor required for Pleiotrophin induced endothelial cell migration through receptor protein tyrosine phosphatase beta zeta
The FASEB Journal, 2009Co-Authors: Constantinos M Mikelis, Marina Koutsioumpa, Evanthia Sfaelou, Nelly Kieffer, Evangelia PapadimitriouAbstract:We have previously shown that the angiogenic growth factor Pleiotrophin (PTN) induces migration of endothelial cells through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta). In this study, we show that a monoclonal antibody against alpha(nu)beta(3) but not alpha(5)beta(1) integrin abolished PTN-induced human endothelial cell migration in a concentration-dependent manner. Integrin alpha(nu)beta(3) was found to directly interact with PTN in an RGD-independent manner, whereas a synthetic peptide corresponding to the specificity loop of the beta(3) integrin extracellular domain ((177)CYDMKTTC(184)) inhibited PTN-alpha(nu)beta(3) interaction and totally abolished PTN-induced endothelial cell migration. Interestingly, alpha(nu)beta(3) was also found to directly interact with RPTPbeta/zeta, and PTN-induced Y773 phosphorylation of beta(3) integrin was dependent on both RPTPbeta/zeta and the downstream c-src kinase activation. Midkine was found to interact with RPTPbeta/zeta, but not with alpha(nu)beta(3), and caused a small but statistically significant decrease in cell migration. In the same line, PTN decreased migration of different glioma cell lines that express RPTPbeta/zeta but do not express alpha(nu)beta(3), while it stimulated migration of U87MG cells that express alpha(nu)beta(3) on their cell membrane. Overexpression or down-regulation of beta(3) stimulated or abolished, respectively, the effect of PTN on cell migration. Collectively, these data suggest that alpha(nu)beta(3) is a key molecule that determines the stimulatory or inhibitory effect of PTN on cell migration.