Endosomal Accumulation of the Activated Epidermal Growth Factor Receptor (EGFR) Induces Apoptosis

Rush, Jamie S.; Quinalty, Leslie M.; Engelman, Luke; Sherry, David M.; Ceresa, Brian P.

doi:10.1074/jbc.m111.294470

Cited by 77 publications

(103 citation statements)

References 27 publications

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“…The authors have used monensin to block endosomal trafficking of EGFR. As EGFR accumulation and activation pattern shown in the current study largely exceeds the magnitude of EGFR accumulation shown previously (37), it is reasonable to propose that cell death is probably the terminal outcome of myoferlin depletion. The present results confirm this and show a strong induction of apoptosis in myoferlin deficient, EGF-stimulated cells.…”

Section: Discussionsupporting

confidence: 55%

“…Same is the case with Raf kinase (36), where high-intensity Raf signal causes cell-cycle arrest; this is in contrast to the normally assumed proproliferation function. Recently, Rush and colleagues (37) have shown that high endosomal accumulation of activated EGFR induces apoptosis in MDA-MB468 cells. The authors have used monensin to block endosomal trafficking of EGFR.…”

Section: Discussionmentioning

confidence: 99%

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Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

et al. 2013

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Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair, and endocytosis. While some reports have implicated myoferlin in cancer, the extent of its expression in and contributions to cancer are not well established. In this study, we show that myoferlin is overexpressed in human breast cancers and that it has a critical role in controlling degradation of the epidermal growth factor (EGF) receptor (EGFR) after its activation and internalization in breast cancer cells. Myoferlin depletion blocked EGF-induced cell migration and epithelial-to-mesenchymal transition. Both effects were induced as a result of impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homo-oligomerization. In parallel, myoferlin depletion reduced tumor development in a chicken chorioallantoic membrane xenograft model of human breast cancer. Considering the therapeutic significance of EGFR targeting, our findings identify myoferlin as a novel candidate function to target for future drug development. Cancer Res; 73(17); 5438-48. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

et al. 2013

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“…Intracellular tyrosine kinase receptor signaling has also been established through studies of EGF receptor (EGFR) endosomal accumulation. One study (63) has identified cell surface EGFRs as promoting cell growth and intracellular EGFRs as inducing apoptosis. Another study (66) has identified the presence of ERK-MAPK components on EGFR-containing endosomes and the presence of ligand-bound EGFRs on endosomes, suggesting the occurrence of EGFR endosomal signaling.…”

Section: Cd31mentioning

confidence: 99%

Endothelial cell-by-cell profiling reveals the temporal dynamics of VEGFR1 and VEGFR2 membrane localization after murine hindlimb ischemia

Imoukhuede

Dokun

Annex

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Imoukhuede PI, Dokun AO, Annex BH, Popel AS. Endothelial cell-by-cell profiling reveals the temporal dynamics of VEGFR1 and VEGFR2 membrane localization after murine hindlimb ischemia. Am J Physiol Heart Circ Physiol 304: H1085-H1093, 2013. First published February 1, 2013 doi:10.1152/ajpheart.00514.2012 cell surface localization plays a critical role in transducing VEGF signaling toward angiogenic outcomes, and quantitative characterization of these parameters is critical to advancing computational models for predictive medicine. However, studies to this point have largely examined intact muscle; thus, essential data on the cellular localization of the receptors within the tissue are currently unknown. Therefore, our aims were to quantitatively analyze VEGFR localization on endothelial cells (ECs) from mouse hindlimb skeletal muscles after the induction of hindlimb ischemia, an established model for human peripheral artery disease. Flow cytometry was used to measure and compare the ex vivo surface localization of VEGFR1 and VEGFR2 on CD31 ϩ /CD34 ϩ ECs 3 and 10 days after unilateral ligation of the femoral artery. We determined that 3 days after hindlimb ischemia, VEGFR2 surface levels were decreased by 80% compared with ECs from the nonischemic limb; 10 days after ischemia, we observed a twofold increase in surface levels of the modulatory receptor, VEGFR1, along with increased proliferating cell nuclear antigen, urokinase plasminogen activator, and urokinase plasminogen activator receptor mRNA expression compared with the nonischemic limb. The significant upregulation of VEGFR1 surface levels indicates that VEGFR1 indeed plays a critical role in the ischemia-induced perfusion recovery process, a process that includes both angiogenesis and arteriogenesis. The quantification of these dissimilarities, for the first time ex vivo, provides insights into the balance of modulatory (VEGFR1) and proangiogenic (VEGFR2) receptors in ischemia and lays the foundation for systems biology approaches toward therapeutic angiogenesis.angiogenesis; peripheral artery disease; endothelial cells; skeletal muscle; quantitative flow cytometry; receptor localization; Quantibrite; hindlimb ischemia; vascular endothelial growth factor receptor THE VEGF RECEPTOR (VEGFR)-ligand family is a key regulator of angiogenesis, the growth of new blood vessels from preexisting microvasculature. VEGF binding to its receptors activates intracellular signaling pathways inducing the endothelial proliferation and migration necessary for angiogenesis. Therapeutic angiogenesis aims to treat ischemic disease through the supplementation of VEGF and/or other angiogenic growth factors (31,48). The use of VEGF has successfully stimulated neovascularization in animal models of ischemia (30, 68). However, the use of VEGFs, fibroblast growth factor, hepatocyte growth factor, and other proangiogenic molecules has not yielded successful clinical outcomes (8,31,34). These clinical setbacks have been attributed to inadequate dosing, duration, and delivery as well a...

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“…HeLa cells express physiological levels of EGFR and are a wellcharacterized model for the study of EGFR trafficking (Ley and Ellem, 1992;Rush et al, 2012). Stimulation of HeLa cells using a range of EGF concentrations caused EGFR activation, as assessed by an increase in phosphorylated ERK1 and ERK2, and high concentration EGF elicited a marked downregulation of EGFR (supplementary material Fig.…”

Section: Ligand Concentration and Rin1 Function Determine Egfr Ubiquimentioning

confidence: 99%

RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR

Balaji¹,

Mooser²,

Janson³

et al. 2012

Journal of Cell Science

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SummaryStimulation of epidermal growth factor receptor (EGFR) initiates RAS signaling simultaneously with EGFR internalization. Endocytosed EGFR is then either recycled or degraded. EGFR fate is determined in part by the RAS effector RIN1, a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. EGFR degradation was slowed by RIN1 silencing, enhanced by RIN1 overexpression and accelerated by RIN1 localization to the plasma membrane. RIN1 also directly activates ABL tyrosine kinases, which regulate actin remodeling, a function not previously connected to endocytosis. We report that RIN1-RAB5 signaling favors EGFR downregulation over EGFR recycling, whereas RIN1-ABL signaling stabilizes EGFR and inhibits macropinocytosis. RIN1QM , a mutant that blocks ABL activation, caused EGF-stimulated membrane ruffling, actin remodeling, dextran uptake and EGFR degradation. An ABL kinase inhibitor phenocopied these effects in cells overexpressing RIN1. EGFR activation also promotes RIN1 interaction with BIN1, a membrane bending protein. These findings suggest that RIN1 orchestrates RAB5 activation, ABL kinase activation and BIN1 recruitment to determine EGFR fate.

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Endosomal Accumulation of the Activated Epidermal Growth Factor Receptor (EGFR) Induces Apoptosis

Cited by 77 publications

References 27 publications

Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer

Endothelial cell-by-cell profiling reveals the temporal dynamics of VEGFR1 and VEGFR2 membrane localization after murine hindlimb ischemia

RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR

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