Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation

Chen, William S.; Lazar, Cheri S.; Lund, Kim; Welsh, John; Chang, Chia Ping; Walton, Gordon M.; Der, Channing J.; Wiley, H. Steven; Gill, Gordon N.; Rosenfeld, Michael G.

doi:10.1016/0092-8674(89)90867-2

Cited by 349 publications

(278 citation statements)

References 39 publications

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“…Thus, unlike wild type receptors, EGFRvIII may be unable to attenuate mitogenic signaling by receptor internalization (Huang et al, 1997). Within the C-terminal region of the EGFR there is a domain designated CAIN which modulates receptor internalization (Chen et al, 1989). Deletion of this region leads to increased transforming ability presumably via prolongation of cell-surface receptor half-life (Wells et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

1998

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Section: Discussionmentioning

confidence: 99%

Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

1998

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“…Their construction was described previously (36). B82 cells were grown in Dulbecco's modified Eagle's medium (Flow Laboratories) containing dialyzed 10% calf serum (HyClone).…”

Section: Methodsmentioning

confidence: 99%

Structural Aspects of the Epidermal Growth Factor Receptor Required for Transmodulation of erbB-2/neu

Worthylake

Wiley

1997

Journal of Biological Chemistry

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The epidermal growth factor receptor (EGF-R) is known to transmodulate the activity and level of the erbB-2/neu protein in several epithelial cell lines. We therefore determined which structural features of the EGF-R were important in transmodulating erbB-2. We found that the addition of EGF to nontransformed epithelial cells resulted in down-regulation of erbB-2 with the same kinetics and similar extent as the EGF-R. By using cells expressing a series of EGF-R modified by site-directed mutagenesis, we found that EGF-R tyrosine kinase activity was not necessary for down-regulation of erbB-2, but receptor sequences between 899 and 958 in the EGF-R were required. To determine whether transmodulation was associated with activation of erbB-2, tyrosine phosphorylation of erbB-2 was determined following addition of EGF. Again, phosphorylation of erbB-2 following EGF addition did not require the intrinsic tyrosine kinase activity of the EGF-R, but did require sequences between 899 and 958. To determine the localization of EGF-R and erbB-2 following EGF addition, the relative distribution of the two receptors was evaluated by fluorescence microscopy. Surprisingly, the majority of erbB-2 was found in small cytoplasmic vesicles, whereas the EGF-R was predominantly found on the cell surface. Addition of EGF resulted in a redistribution and consequent colocalization of both receptors in endosomal and lysosomal structures. We conclude that activation and transmodulation of erbB-2 does not require intrinsic tyrosine kinase activity of the EGF-R, but does require sequences in the EGF-R which regulate its trafficking.

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“…Biochemical and morphological studies that utilized a kinase-defective mutant of ErbB-1 revealed causal relationships between receptor occupancy, kinase activity, and the rate of internalization (Honegger et al 1987;Chen et al 1989;Hopkins et al 1990). However, the role played by the catalytic activity of ErbB-1 in lysosomal targeting is currently unclear.…”

Section: Genes and Developmentmentioning

confidence: 99%

c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor

Levkowitz¹,

Waterman²,

Zamir³

et al. 1998

Genes Dev.

774

745

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Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors.

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Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation

Cited by 349 publications

References 39 publications

Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

Structural Aspects of the Epidermal Growth Factor Receptor Required for Transmodulation of erbB-2/neu

c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor

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