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- Title
Identification of pl85<sup>neu</sup> Sequences Required for Monoclonal Antibody- or Ligand-Mediated Receptor Signal Attenuation.
- Authors
QIAN, XIAOLAN; O'ROURKE, DONALD M.; DREBIN, JEFFREY; ZHAO, HUIZHEN; WANG, QIANG; GREENE, MARK I.
- Abstract
Anti-pl85neu antibodies downmodulate constitutively active pl85neu receptors from the cell surface, which is associated with a reduction in the transformed phenotype. We have analyzed a group of mutant pl85neu forms with carboxyl (C)-terminal truncations and/or an internal deletion of amino acids 1008-1057. Receptor endocytosis and degradation were examined by flow cytometric analysis and pulse-chase assays following antipl85neu monoclonal antibody (MAb) treatment. Deletion of a sequence within the distal carboxyl terminus, including three known autophosphorylation sites, did not affect MAb-mediated receptor surface downmodulation and degradation of surface receptor. However, kinase-active deletion mutants with elimination of the putative internalization sequence (TintΔ), or TintΔ mutants also containing a large C-terminal truncation, displayed markedly impaired receptor endocytosis in response to MAb treatment. Cells expressing endocytosis-defective mutant proteins became insensitive to anti-pl85neu MAb-mediated inhibition of anchorage-independent growth and were more oncogenic in vivo. Cells expressing endocytosis-defective mutant EGFR/neu chimeric proteins were more transforming upon EGF addition when compared to cells expressing wild-type EGFR/neu receptors. Taken together, these data suggest that, in addition to kinase activity, pl85neu receptor endocytosis requires a functional modular structure, i.e., an internalization sequence, possibly to serve as target for endocytotic adapter proteins. Unattenuated signaling from oncogenic pl85neu forms resulting from prolonged surface localization may result in enhanced cellular transformation and desensitization to MAbmediated downregulation and phenotypic reversion.
- Publication
DNA & Cell Biology, 1997, Vol 16, Issue 12, p1395
- ISSN
1044-5498
- Publication type
Article
- DOI
10.1089/dna.1997.16.1395