Disease relevance of Ptn

• Mechanistically, hypoxia and PDGF mediated induction of PTN expression in sinusoidal HSCs may provide a strong mitogenic signal for hepatocytes to limit the damage to the parenchymal cells in biliary-type liver fibrogenesis [1].
• MATERIALS AND METHODS: We investigated the expression of the angiogenic factor pleiotrophin/HB-GAM in a closed fracture model in rats by immunohistochemical methods [2].
• We now demonstrate that Ptn gene expression is strikingly upregulated within 3 d in OX42-positive macrophages, astrocytes, and endothelial cells in areas of developing neovasculature after focal cerebral ischemia in adult rat [3].
• MK expression was upregulated two to threefold correlating with disease progression, whereas PTN expression reached peak levels threefold above basal levels during the clinical recovery period [4].
• Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin [4].

High impact information on Ptn

• Our hypothesis that HB-GAM/N-syndecan interaction participates in regulation of osteoblast recruitment was tested using two different in vivo models: an adjuvant-induced arthritic model and a transgenic model [5].
• We show here that heparin-binding growth-associated molecule (HB-GAM), an extracellular matrix-associated protein that enhances migratory responses in neurons, is prominently expressed in the cell matrices that act as target substrates for bone formation [5].
• The HB-GAM transgenic mice develop a phenotype characterized by an increased bone thickness [5].
• Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growth-associated molecule (HB-GAM) [5].
• In the adjuvant-induced injury model, the expression of HB-GAM and of N-syndecan is strongly upregulated in the periosteum accompanying the regenerative response of bone [5].

Biological context of Ptn

• Heparin-binding proteins HB-GAM (pleiotrophin) and amphoterin in the regulation of cell motility [6].
• Structural studies using heteronuclear NMR reveal two similar protein domains in HB-GAM, both consisting of three anti-parallel beta-strands [6].
• The HB-GAM sequence clearly (about 50%) is homologous to that of MK (midkine) sequence, a protein discovered through screening for factors that mediate retinoic acid-induced cell differentiation [7].
• In addition to enhancing neurite growth in a developmentally regulated manner in early neurons, HB-GAM is accumulated at the growth cone-target interphase accompanying the onset of synaptogenesis, as evidenced by its presence at the neuromuscular junction of Xenopus and rat [7].
• 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 [8].

Anatomical context of Ptn

• HSCs expressed PTN mRNA in response to GalN treatment and its protein was found on hepatocytes [9].
• We suggest that the TSR sequence motif, found in several neurite outgrowth-promoting and other cell surface and matrix-binding proteins, defines a beta structure similar to those found in HB-GAM and MK [6].
• HB-GAM is suggested to regulate motility in osteoblasts through a similar mechanism as in neurons [6].
• These findings, together with in vitro interactions with neurons, suggest that HB-GAM is a cell matrix-associated cue for growth cone migration [7].
• In the transgenic model, the HB-GAM expression is maintained in mesenchymal tissues with the highest expression in the periosteum [5].

Associations of Ptn with chemical compounds

• The expression of PTN mRNA in the liver was markedly up-regulated by the treatment with D-galactosamine (GalN) or with acetylaminofluorene followed by partial hepatectomy [9].
• In addition to N-syndecan, the chondroitin sulfate proteoglycan RPTP beta/zeta (receptor-type tyrosine phosphatase beta/zeta) is implicated in the receptor mechanism of HB-GAM [6].
• The data indicate that PTN is up-regulated in DA-depleted striatum and exhibits a trophic effect specifically on the survival of cultured dopaminergic neurons [10].
• As PTN did not increase the number of microtubule-associated protein-2 (MAP 2)-positive neurons or promote the proliferation of dopaminergic progenitors in a bromodeoxyuridine (BrdU) labelling study, the effect appeared to enhance the specific survival of dopaminergic neurons [10].
• We showed that the domains (but not the lysine-rich tails) in HB-GAM are required and sufficient for interaction with hippocampal neurons [11].

Regulatory relationships of Ptn

• Biochemical and cell biological studies have previously identified N-syndecan as a neuronal cell surface receptor in neurite outgrowth induced by heparin-binding growth-associated molecule (HB-GAM) [12].

Other interactions of Ptn

• The mRNA expression of N-syndecan, a PTN receptor, was up-regulated in GalN-treated hepatocytes [9].
• HB-GAM is a secretory, extracellular matrix-associated protein that was isolated by screening for factors that enhance neurite outgrowth in rat brain neurons [7].
• Further double-immunolabeling studies ruled out PTN localization to calretinin- and parvalbumin-containing interneurons [13].
• The two thrombospondin type I repeat domains of the heparin-binding growth-associated molecule bind to heparin/heparan sulfate and regulate neurite extension and plasticity in hippocampal neurons [11].
• In a simple pathway assay, E13 raphe neurones selectively preferred attaching and growing neurites on pathways containing HB-GAM as compared with regions containing either laminin or fibronectin alone [14].

Analytical, diagnostic and therapeutic context of Ptn

• HSCs expressed PTN mRNA and secreted its protein in the co-cultures [9].
• The increase in PTN mRNA was confirmed by Northern blotting at 1-3 weeks after the lesion, reaching a peak at 1 week [10].
• The microarray analysis revealed that pleiotrophin (PTN), glial-derived neurotopic factor (GDNF) and others were up-regulated in DA-depleted striatum [10].
• In the present study we have compared temporal and spatial expression patterns of N-syndecan and HB-GAM using Northern and Western blotting and immunohistochemistry [12].
• Using in situ hybridization, thalamic neurons were shown to express mRNA for N-syndecan, and in vitro, thalamic neurons grew more neurites on HB-GAM than on laminin [15].

References