Exogenous pleiotrophin applied to lesioned nerve impairs muscle reinnervation.

Pleiotrophin (PTN) is a heparin-binding growth factor involved in nerve regeneration after peripheral nerve injury. After crush injury, PTN is found in distal nerve segments in several non-neural cell types, including Schwann cells, macrophages, and endothelial cells, but not in axons. To further clarify the role for PTN in nerve regeneration, we investigated the effects of PTN applied to lesioned peripheral nerve in vivo. PTN in a dose of 1 mg/kg impaired muscle reinnervation. Thus, gastrocnemius muscle failed to recover its contractile properties as assessed by in situ maximal isometric tetanic force. PTN also decreased non-neural cell densities and delayed macrophage recruitment in the distal crushed nerve. These results are discussed in the light of recent evidence that PTN is a multifunctional polypeptide

Exogenous pleiotrophin applied to lesioned nerve impairs muscle reinnervation.

Pleiotrophin (PTN) is a heparin-binding growth factor involved in nerve regeneration after peripheral nerve injury. After crush injury, PTN is found in distal nerve segments in several non-neural cell types, including Schwann cells, macrophages, and endothelial cells, but not in axons. To further clarify the role for PTN in nerve regeneration, we investigated the effects of PTN applied to lesioned peripheral nerve in vivo. PTN in a dose of 1 mg/kg impaired muscle reinnervation. Thus, gastrocnemius muscle failed to recover its contractile properties as assessed by in situ maximal isometric tetanic force. PTN also decreased non-neural cell densities and delayed macrophage recruitment in the distal crushed nerve. These results are discussed in the light of recent evidence that PTN is a multifunctional polypeptide

Adult Brain but Not Kidney, Liver, Lung, Intestine, and Stomach Membrane Preparations Contain Detectable Amounts of High-Affinity Receptors to Acidic and Basic Growth Factors

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High Affinity Receptors to Acidic and Basic Fibroblast Growth Factor (FGF) are Detected Mainly in Adult Brain Membrane Preparations but not in Liver, Kidney, Intestine, Lung or Stomach

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USE OF MULTIVALENT SYNTHETIC LIGANDS OF SURFACE NUCLEOLIN FOR TREATING CANCER OR INFLAMMATION

A method for treating disorders involving deregulation of cell proliferation and/or angiogenesis comprising the administration of an effective amount of a multivalent synthetic compound comprising a support on which at least 3 pseudopeptide units are grafted, said compound being of formula (I)

Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor

Background: Receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPβ/ζ interacts with ανβ3 on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β3 Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β3 Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF165) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - ανβ3 integrin association and subsequent signaling. In the present work, we studied whether RPTPβ/ζ mediates angiogenic actions of VEGF. Methods: Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different β3 subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPβ/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 μm pores. Results: RPTPβ/ζ mediates VEGF165-induced c-Src-dependent β3 Tyr773 phosphorylation, which is required for VEGFR2-ανβ3 interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF165, and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPβ/ζ by siRNA or administration of exogenous CS-E abolishes VEGF165-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF165 to the levels of its own effect. Conclusions: These data identify RPTPβ/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for development of additive or alternative anti-VEGF therapies

Cellular Distribution of the Angiogenic Factor Heparin Affin Regulatory Peptide (HARP) mRNA and Protein in the Human Mammary Gland

The heparin affin regulatory peptide (HARP) growth factor, also known as pleiotrophin, is a developmentally regulated protein that displays biological functions during cell growth and differentiation. To study the physiological role of this protein, we investigated the cellular distribution of HARP mRNA and protein in the resting human mammary gland. In situ hybridization histochemistry revealed that HARP mRNA was localized in alveolar myoepithelial cells, whereas alveolar epithelial cells were negative. In the stroma, HARP mRNA was localized in endothelial cells and smooth muscle cells of blood vessels. Interestingly, HARP protein and mRNA were not always co-localized. HARP protein immunocytochemistry staining was observed in an area including both alveolar myoepithelial and epithelial cells, although epithelial cells do not express HARP transcript. In contrast, the distribution of HARP protein is parallel to that of HARP mRNA in endothelial and vascular smooth muscle cells. In the light of these results, the putative role of HARP in controlling the proliferation and/or differentiation of the different mammary cell types is proposed and discussed