Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor tyrosine kinases (RTKs) are grouped into subcategories based on shared sequence and structural features. Human group C adenoviruses down-regulate EGF receptors, which are members of the class I family of RTKs, during the early stages of infection. Adenovirus appears to utilize a nonsaturable intracellular pathway since it causes EGF-R down-regulation even in cells that significantly overexpress EGF-R. Adenovirus-induced down-regulation is mediated by a small hydrophobic molecule coded for by the E3 early transcription region that has recently been localized to plasma membrane. Here we examine intracellular trafficking of other RTKs in adenovirus-infected cells, to better understand the molecular basis for the action of the E3 protein. Although p185c-neu, which is a class I RTK closely related to the EGF receptor, is down-regulated in cells expressing physiological concentrations of this molecule, it is not down-regulated in tumor cell lines that significantly overexpress p185c-neu. Cell surface receptors for insulin and IGF1, which are class II RTKs, are also reduced in cells expressing the E3 protein, although to a slightly lesser extent than the EGF receptor. Moreover, whereas EGF receptors are degraded between 3- and 9-h postinfection, insulin and IGF1 receptors are degraded between 6- and 12-h postinfection under identical conditions. In contrast to the class I and class II RTKs, there is no difference in the expression of the class III receptors for PDGF and aFGF in cells infected with a virus with an intact E3 region versus a virus mutant with an internal deletion in the relevant E3 gene. These results suggest that the E3 protein provides an internalization and degradative sorting signal for some class I and class II RTKs, although down-regulation of class II RTKs is somewhat less efficient. Molecular recognition of class I and class II RTKs during adenovirus infection may not be due strictly to amino acid structure, however, since EGF-R but not p185c-neu is down-regulated in cells where it is significantly overexpressed.
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PMID:Structurally related class I and class II receptor protein tyrosine kinases are down-regulated by the same E3 protein coded for by human group C adenoviruses. 809 18

Vectors based on Adenovirus type 5 (Ad5) are among the most common vectors in cancer gene therapy trials to date. However, for increased efficiency and safety, Ad5 should be de-targeted from its native receptors and re-targeted to a tumor antigen. We have described earlier an Ad5 vector genetically re-targeted to the tumor antigen HER2/neu by a dimeric version of the Affibody molecule ZH inserted in the HI-loop of the fiber knob of a coxsackie and adenovirus receptor-binding ablated fiber. This virus showed almost wild-type growth characteristics and infected cells through HER2/neu. Here we generate vectors with double specificity by incorporating two different Affibody molecules, ZH (HER2/neu-binding) and ZT (Taq polymerase-binding), at different positions relative to one another in the HI-loop. Receptor-binding studies together with viral production and gene transfer assays showed that the recombinant fiber with ZT in the first position and ZH in the second position (ZTZH) bound to both its targets, whereas surprisingly, the fiber with ZHZT was devoid of binding to HER2/neu. Hence, it is possible to construct a recombinant adenovirus with dual specificity after evaluating the best position for each ligand in the fiber knob.
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PMID:Re-targeted adenovirus vectors with dual specificity; binding specificities conferred by two different Affibody molecules in the fiber. 1894 96