Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor protein tyrosine phosphatase beta (RPTP beta) mediates cell-cell and cell-matrix interactions. By searching for intracellular proteins that interact with the cytoplasmic region of this phosphatase using the two-hybrid method, we identified several proteins containing PDZ domains. One of these proteins, MAGI-3, contains a guanylate-kinase-like region, six PDZ and two WW domains. The interaction between RPTP beta and MAGI-3 was confirmed by co-immunoprecipitation and pulldown experiments in transfected cells. Immunofluorescence and immunoelectron microscopy revealed that MAGI-3 is concentrated in specific sites at the plasma membrane and in the nucleus. In epithelial cells, MAGI-3 was localized with ZO-1 and cingulin at tight junctions, whereas in primary cultured astrocytes it was found in E-cadherin-based cell-cell contacts and in focal adhesion sites. Although MAGI-3 itself was not phosphorylated on tyrosine residues, it became associated with tyrosine-phosphorylated proteins following a short treatment of the cells with vanadate. In glioblastoma SF763T cells MAGI-3 was associated with a tyrosine-phosphorylated protein with the apparent molecular weight of 130 kDa, whereas in Caco2 cells it was associated with a 90 kDa protein. Finally, we show that p130 served as a substrate for RPTP beta and that its dephosphorylation required the C-terminal sequence of the phosphatase, which mediated the interaction with MAGI-3. These findings suggest a possible role for MAGI-3 as a scaffolding molecule that links receptor tyrosine phosphatase with its substrates at the plasma membrane.
 ...
PMID:Junctional protein MAGI-3 interacts with receptor tyrosine phosphatase beta (RPTP beta) and tyrosine-phosphorylated proteins. 1261 70

Using subtractive cloning combined with cDNA array analysis, we previously identified the genes encoding for the protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) as overexpressed in human glioblastomas compared to normal brain. Both molecules have been implicated in neuronal migration during central nervous system development, and PTN is known to be involved in tumor growth and angiogenesis. We confirm overexpression of both molecules at the protein level in astrocytic gliomas of different malignancy grades. PTPzeta/RPTPbeta immunoreactivity was associated with increasing malignancy grade and localized predominantly to the tumor cells. PTN immunoreactivity as determined by ELISA and immunohistochemistry analysis was increased in low-grade astrocytomas compared to normal brain. Further increase in malignant gliomas was marginal, and thus no correlation with malignancy grade or microvessel density was present. However, PTN levels were significantly associated with those of fibroblast growth factor-2, suggesting co-regulation of both factors. Functionally, PTN induced weak chemotactic and strong haptotactic migration of glioblastoma and cerebral microvascular endothelial cells. Haptotaxis of glioblastoma cells towards PTN was specifically inhibited by an anti-PTPzeta/RPTPbeta antibody. Our findings suggest that upregulated expression of PTN and PTPzeta/RPTPbeta in human astrocytic tumor cells can create an autocrine loop that is important for glioma cell migration. Although PTN is a secreted growth factor, it appears to exert its mitogenic effects mostly in a matrix-immobilized form, serving as a substrate for migrating tumor cells.
 ...
PMID:Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. 1469 2

The protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) are overexpressed in human glioblastomas. Both molecules are involved in neuronal cell migration during CNS development. In addition, PTN can induce glioma cell migration which is at least in part mediated through binding to PTPzeta/RPTPbeta. To study the relevance of this ligand-receptor pair for glioma growth in vitro and in vivo, we transfected the human glioblastoma cell line U251-MG with small interfering RNA (siRNA) directed against PTPzeta/RPTPbeta. Stable siRNA transfection resulted in strong down-regulation of PTPzeta/RPTPbeta expression. When injected subcutaneously into nude mice, clones that expressed normal levels of PTPzeta/RPTPbeta (PTPzeta + clones) formed exponentially growing tumours, whereas tumour growth was almost completely abrogated for clones that expressed reduced PTPzeta/RPTPbeta levels (PTPzeta - clones). Similar results were obtained using an orthotopic intracerebral model. Proliferation of PTPzeta - cells in vitro was significantly reduced compared with that of control clones. Matrix-immobilized PTN stimulated the proliferation of PTPzeta + cells but not of PTPzeta - cells. Haptotactic migration induced by PTN was reduced for PTPzeta - clones compared with control clones. Our findings suggest that antagonization of PTPzeta/RPTPbeta expression can inhibit glioma growth in vivo and may thus represent a potentially promising treatment strategy.
 ...
PMID:RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. 1692 62