PubMed · 4319086
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A J Beale. 1969. Immunization against poliomyelitis.. https://doi.org/10.1093/oxfordjournals.bmb.a070684
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In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.
The Delta pH pathway is one of two systems for protein transport to the thylakoid lumen. It is a novel transport system that requires only the thylakoidal DeltapH to power translocation. Several substrates of the Delta pH pathway, including the intermediate precursor form of OE17 (iOE17) and the truncated precursor form of OE17 (tOE17), were shown to bind to the membrane in the absence of the DeltapH and be transported into the lumen when the DeltapH was restored. Binding occurred without energy or soluble factors, and efficient transport from the bound state ( approximately 80-90%) required only the DeltapH. Binding is due to protein-protein interactions because protease pretreatment of thylakoids destroyed their binding capability. Precursors are bound to a specific site on the Delta pH pathway because binding was competed by saturating amounts of Delta pH pathway precursor proteins, but not by a Sec pathway precursor protein. These results suggested that precursor tOE17 binds to components of the Delta pathway translocation machinery. Hcf106 and Tha4 are two components of the Delta pH pathway machinery. Antibodies to Hcf106 or Tha4, when prebound to thylakoids, specifically inhibited precursor transport on the Delta pH pathway. However, only Hcf106 antibodies reduced the level of precursor binding. These results suggest that Hcf106 functions in early steps of the transport process.
Platelet function is influenced by the platelet thiol-disulfide balance. Platelet activation resulted in 440% increase in surface protein thiol groups. Two proteins that presented free thiol(s) on the activated platelet surface were protein-disulfide isomerase (PDI) and glycoprotein 1balpha (GP1balpha). PDI contains two active site dithiols/disulfides. The active sites of 26% of the PDI on resting platelets was in the dithiol form, compared with 81% in the dithiol form on activated platelets. Similarly, GP1balpha presented one or more free thiols on the activated platelet surface but not on resting platelets. Anti-PDI antibodies increased the dissociation constant for binding of vWF to platelets by approximately 50% and PDI and GP1balpha were sufficiently close on the platelet surface to allow fluorescence resonance energy transfer between chromophores attached to PDI and GP1balpha. Incubation of resting platelets with anti-PDI antibodies followed by activation with thrombin enhanced labeling and binding of monoclonal antibodies to the N-terminal region of GP1balpha on the activated platelet surface. These observations indicated that platelet activation triggered reduction of the active site disulfides of PDI and a conformational change in GP1balpha that resulted in exposure of a free thiol(s).