Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation

Grøvdal, Lene Melsæther; Stang, Espen; Sorkin, Alexander; Madshus, Inger Helene

doi:10.1016/j.yexcr.2004.07.003

Cited by 160 publications

(157 citation statements)

References 182 publications

(249 reference statements)

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“…6E) (76), there was no noticeable downregulation of EGFR in response to the cytokine. It is possible that TNF may not stimulate phosphorylation on specific EGFR tyrosines that drive receptor internalization (24). It is also possible that, because of differences in localization or kinetics of phosphorylation, TNF-transactivated EGFR does not result in the activation of proteins that are involved in the downregulation of EGFR.…”

Section: Discussionmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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Section: Discussionmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…1B). In general, a receptor dimer containing EGFR tends to show a transient pattern of the receptor phosphorylation, because an activated EGFR is down-regulated by Cbl ubiquitination and lysosomal degradation (11,23). It is known that mutation of the Cbl-binding site at Tyr-1045 on the EGFR abolishes the ubiquitination and enhances rapid recycling of the receptor (23).…”

Section: Egf and Hrg Induce Different Kinetics Of Intracellularmentioning

confidence: 99%

Quantitative Transcriptional Control of ErbB Receptor Signaling Undergoes Graded to Biphasic Response for Cell Differentiation

Nagashima¹,

Shimodaira

Ide³

et al. 2007

Journal of Biological Chemistry

161

146

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The different kinetics displayed by extracellular signal-regulated kinase (ERK) 3 activation often results in distinct cellular phenotypes of mammalian cells. In PC12 cells, the epidermal growth factor (EGF)-stimulated transient activation of ERK induces cell proliferation, whereas a nerve growth factor-stimulated sustained activation of ERK induces differentiation (1, 2). Similarly, different growth factor ligands cause distinct kinetics of ERK activation in human breast cancer cells (3, 4). ERK and Akt/protein kinase B are deterministic kinases that control the activation of nuclear transcription factors (5-7); therefore, it is expected that the activation kinetics of these kinases might affect the following gene expression profiles. However, the question concerning gene expression dynamics induced by kinetically different kinase activities and its effect on cell determination mechanisms remains unsolved.In this study we focused on the dose-dependent time course analysis of early transcription induced by two ligands of the ErbB family receptor, EGF and heregulin (HRG), which induce distinct kinase activity patterns and phenotypes of MCF-7 cells. Although many studies attempted to delineate the biochemical characteristics of ErbB ligands and receptors, no systematic study has been reported concerning the analysis of ErbB receptor-mediated cell fate control.MCF-7 cells endogenously express all family members of the ErbB protein-tyrosine kinase receptors (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4 receptors). EGF preferably binds to an EGFR, whereas HRG first binds to either the ErbB3 or ErbB4 receptor and then induces trans-activation of ErbB2 (8). ErbB receptors tend to form heterodimers in response to ligand binding when different ErbB receptors are co-expressed in the same cell. In particular, ErbB2 is the preferred heterodimerization partner among the receptor family (9), and it functions as an oncogenic unit through heterodimer formation with ErbB3 (10). EGFR activation induces selfdown-regulation of the receptor by recruitment of the Cbl ubiquitin ligase (11,12), and the activation of ErbB3 strongly evokes phosphatidylinositol 3Ј-kinase (PI3K) activation (13,14). Activation of ErbB receptor is often accompanied by activation of Shc-ERK and PI3K-Akt pathways. These two pathways often cross-talk or inhibit each other (15, 16) thereby resulting in distinct activity patterns pertaining to intracellular signaling that activate various types of transcription factors (17-19). In addition, many studies attempted to identify specific gene expression induced by different ErbB ligands that show signaling diversities and distinct biological outcomes (20, 21); however, earlier results using platelet-derived growth factor (PDGF)-␤ receptor mutants indicated that diverse signaling pathways induce broadly overlapping transcription (22).

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“…Cbl also forms a complex with CIN85 and endophilin to regulate internalization of ligand-bound EGFR (5). Cbl is recruited to the receptor in response to EGF stimulation by direct binding to phosphotyrosine 1045 of the EGFR (6,7). Cbl also binds indirectly to the EGFR through the Grb2 adaptor protein (8 -10).…”

Section: Ligand-induced Endocytosis Of the Epidermal Growth Factor Rementioning

confidence: 99%

Abl Tyrosine Kinase Regulates Endocytosis of the Epidermal Growth Factor Receptor

Tanos

Pendergast

2006

Journal of Biological Chemistry

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Signal attenuation from ligand-activated epidermal growth factor receptor (EGFR) is mediated in part by receptor endocytosis and trafficking to the lysosomal degradative compartment. Uncoupling the activated EGFR from endocytosis and degradation has emerged as a mechanism for oncogenic activation of the EGFR. The Abl nonreceptor tyrosine kinase is activated by ligand-stimulated EGFR, but the role of Abl in EGFR signaling has not been defined. Here we uncovered a novel role for the activated Abl kinase in the regulation of EGFR endocytosis. We show that activated Abl impairs EGFR internalization. Moreover, we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173, and that mutation of this site to phenylalanine restores ligand-dependent endocytosis of the EGFR in the presence of activated Abl. Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR⅐Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human tumors.

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Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation

Cited by 160 publications

References 182 publications

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Quantitative Transcriptional Control of ErbB Receptor Signaling Undergoes Graded to Biphasic Response for Cell Differentiation

Abl Tyrosine Kinase Regulates Endocytosis of the Epidermal Growth Factor Receptor

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