Disease relevance of Ptn

• PTN is highly expressed in favorable neuroblastomas (stages I, II, and IV-S, n = 44), whereas it is expressed at a significantly lower level in advanced tumors (stages III and IV, n = 28, P = 0.003) [1].
• Ribozyme-targeting reveals the rate-limiting role of pleiotrophin in glioblastoma [2].
• Involvement of heparin affin regulatory peptide in human prostate cancer [3].
• Female infertility in mice deficient in midkine and pleiotrophin, which form a distinct family of growth factors [4].
• In human melanoma cells that express high levels of PTN mRNA, stable transfection with PTN-targeted ribozymes quenched production of PTN, inhibited colony formation of the cells, and prevented their tumor growth in mice [5].

High impact information on Ptn

• In humans, elevated serum pleiotrophin levels were found in patients with pancreatic cancer (n = 41; P<.0001) and colon cancer (n = 65; P = .0079) but not in patients with stomach cancer (n = 87; P =.42) [6].
• When ligated by heparin-binding (HB) growth-associated molecule (GAM; pleiotrophin), N-syndecan mediates cortactin-Src kinase-dependent neurite outgrowth [7].
• Pleiotrophin (PTN) is an 18-kDa heparin-binding secretory growth/differentiation factor for different cell types [8].
• We have now used homologous recombination to introduce the dominant-negative PTN mutant into embryonic stem cells to generate chimeric mice [8].
• A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice [8].

Chemical compound and disease context of Ptn

• Heparin affin regulatory peptide (HARP) is an heparin-binding growth factor, highly expressed in several primary human tumors and considered as a rate-limiting angiogenic factor in tumor growth, invasion, and metastasis [9].
• Tetracycline-regulated ribozyme expression vectors were used to deplete conditionally PTN mRNA from melanoma xenograft tumors in vivo [10].
• The expression of HB-GAM studied in 12 cell lines was restricted to C6 rat glioma cell line and BALB/c 3T3 cells [11].
• Pleiotrophin, a ligand for Ptprz, increased tyrosine phosphorylation of p190 RhoGAP in B103 neuroblastoma cells [12].

Biological context of Ptn

• Differences in levels of Mk gene expression in Ptn -/- mice could not be detected in any of the organs tested [13].
• We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development [14].
• Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression [14].
• Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling [15].
• OSF-1 is a 15-kD secreted protein specifically expressed in bone and brain, and is believed to play a role in brain development and osteogenesis [16].

Anatomical context of Ptn

• PTN also transforms NIH 3T3 cells, and MK is mitogenic to certain cell lines [1].
• The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins [14].
• MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions [14].
• Unlike heparin-binding growth-associated molecule (HB-GAM), another member of this growth factor family, MK expression cannot be detected in the muscle but is present in spinal cord neurites [17].
• Here we demonstrate the biologic relevance of PTN in 2 glioblastoma cell lines in vitro and in vivo [2].

Associations of Ptn with chemical compounds

• These results suggest that syndecans are expressed primarily in reactive astrocytes, and may provide a supportive environment for regenerating axons in concert with heparin-binding growth factors (e.g., FGF and PTN) in the injured brain [18].
• 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 [19].
• In vivo treatment with PTN (20 ng/g) increased bromodeoxyuridine incorporation (by 2.24-fold) and PCNA expression (by 1.71-fold) during day 7 to day 14, indicating that PTN induces cell proliferation in mouse heart [20].
• Heparin-binding growth factor, pleiotrophin, mediates neuritogenic activity of embryonic pig brain-derived chondroitin sulfate/dermatan sulfate hybrid chains [21].
• Oversulfated disaccharides and nonconsecutive iduronic acid-containing units were the requirements for the E-CS/DS chains to bind PTN and to exhibit the neuritogenic activities [21].

Physical interactions of Ptn

• These findings supported the hypothesis that parts of the MK and HB-GAM are translocated to the nucleus after binding with nucleolin [22].
• Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to pleiotrophin [23].
• Pleiotrophin has been demonstrated to bind to protein-tyrosine phosphatase zeta (PTPzeta) with high affinity [23].
• This competition may result in the presentation of perlecan-bound growth factors such as HB-GAM to effect synaptic induction [24].

Regulatory relationships of Ptn

• Both perlecan and DG are clustered at ACh receptor clusters induced by spinal neurons or by beads coated with HB-GAM, a heparin-binding growth factor [24].
• Correlation of overall expression patterns between different retinal cell markers and Ptn in situ hybridization suggest that Ptn transcripts are initially expressed in progenitor cells then in postmitotic precursors of the INL expressing the Chx10 gene, and later in some differentiated retinal M??ller glial (RMG) cells and rod-bipolar cells [25].
• The expression of Nurr1 mRNA was enhanced by PTN [26].
• Heparin-binding growth-associated molecule is a developmentally regulated extracellular matrix protein promoting neurite outgrowth, axonal guidance and synaptogenesis [27].
• Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells [26].

Other interactions of Ptn

• The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues [14].
• In our model, FGF receptor1 (FGFR1) and PTN mRNA levels were upregulated in reactive astrocytes [18].
• The involvement of the core protein was also shown in the binding of MK and PTN to syndecan-1, suggesting the possibility of cooperation with the HS and/or CS chains in the binding of these growth factors and their delivery to the cell surface receptors [28].
• These results suggested that PTPzeta is a common receptor for midkine and pleiotrophin [23].
• Further, our in vitro studies show that exogenously added HB-GAM inhibits formation and growth of FGF-2, but not EGF, stimulated neurospheres, restricts the number of nestin-positive neural stem cells, and inhibits FGF receptor phosphorylation [29].

Analytical, diagnostic and therapeutic context of Ptn

• In a subcutaneous tumor xenograft mouse model, in vivo growth is markedly reduced upon PTN depletion, which is paralleled by decreased PTN serum levels [2].
• CONCLUSIONS: MK and PTN are involved both in the inflammatory and reparative processes after partial hepatectomy, and as a whole are beneficial for liver regeneration [30].
• A 15.3-kDa protein detected only in the conditioned medium of neural stem cells was determined as pleiotrophin (PTN) by SELDI-TOF-MS and ProteinChip-tandem MS systems [31].
• Overexpression of Ptn by in vitro electroporation of P0 rat retinal explants partially blocks rod differentiation and promotes bipolar cell production, similar to effects of exogenous CNTF and leukemia inhibitory factor (LIF) [25].
• An unusual effect of PTN (50 ng/ml) was the induction of type I collagen synthesis by chondrocytes in organ cultures of chick nasal cartilage and rat growth plates [32].

References