A role of Rab7 in stabilizing EGFR‐Her2 and in sustaining Akt survival signal

Wang, Tuanlao; Ming, Zhang; Ma, Zexu; Guo, Ke; Tergaonkar, Vinay; Zeng, Qi; Hong, Wanjin

doi:10.1002/jcp.23023

Cited by 46 publications

(37 citation statements)

References 58 publications

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“…Firstly, cells were treated with EGF to induce EGFR accumulation in early endosomes and secondly cells were incubated with fluorescently labeled EGF on ice 9. Incubating cells with EGF at 4°C for 30 min allows the ligand to bind to surface receptors without inducing internalization 34.…”

Section: Resultsmentioning

confidence: 99%

“…Proteins regulating RTK endocytosis have also been implicated in cancer 8 including Rab7 9, Rab5 10 and the E3 ligase C-cbl 11, 12. Rab7 has been shown to affect cell survival and adhesion via co-ordination of the later stages of endocytosis 9.…”

Section: Introductionmentioning

confidence: 99%

“…Rab7 has been shown to affect cell survival and adhesion via co-ordination of the later stages of endocytosis 9. Rab7 has additionally been shown to have a role in endocytosis and cancer through its interaction with Breast Cancer Associated gene 2 (BCA2).…”

Section: Introductionmentioning

confidence: 99%

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The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

Wymant¹,

Hiscox²,

Westwell³

et al. 2016

J. Cancer

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Breast Cancer Associated gene 2 (BCA2) is an E3 ubiquitin ligase that is over-expressed in >50% of primary breast cancers, and has been shown to increase in vitro cell proliferation and invasion. The protein has been linked to alterations in EGFR degradation; however there is some dispute as to its role and influence on the biology of this receptor. Our work aimed to ascertain the role of BCA2 in EGFR endocytosis and down-regulation and to examine its links with breast cancer outcome. Data generated with the online expression analysis tool KM-Plotter showed that high BCA2 levels are associated with poor prognosis in ovarian, gastric and breast cancer, particularly HER2 over-expressing breast cancers. Experimentally, we demonstrate that over-expression of BCA2 induced a reduction in total EGFR levels. BCA2 over-expressing cells stimulated with EGF exhibited reduced lysosomal degradation of both this ligand and its receptor. Signalling downstream of EGFR in BCA2 over-expressing cells was characterized by a lower magnitude but increased duration. Our findings support a role for BCA2 in receptor endocytosis. Consistent with this we show that BCA2 over-expression reduces the level of vesicle-associated Rab7, a regulator of late endocytosis and documented interaction partner of BCA2. Levels of transferrin receptor and the uptake of transferrin were unaltered by over-expression of BCA2 indicating that trafficking changes may be limited to late endocytic sorting events. This report offers a thorough exploration of BCA2 biology and suggests a context-dependent role for the protein in the endocytic regulation of EGFR and as a prognostic biomarker in cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

Wymant¹,

Hiscox²,

Westwell³

et al. 2016

J. Cancer

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“…Inhibition of Hsp90 in HER2-overexpressing cells resulted in degradation of HER2 protein and subsequent inactivation of downstream signaling including the PI3K-AKT pathway [9,10]. In addition to Hsp90, HER2 expression is also protected by Rab7, a GTPase that regulates endocytosis, as loss of Rab7 resulted in proteasome-mediated degradation of HER2 [11]. Thus, the proteins that maintain HER2 overexpression also help maintain suppression of apoptosis by HER2 signaling.…”

Section: Her2 Regulation Of Apoptosismentioning

confidence: 99%

Regulation of Apoptosis by HER2 in Breast Cancer

Carpenter

2013

J Carcinog Mutagen

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HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.

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“…Mechanistically, downregulation of SNX1 drives endocytosis-dependent activation of EGFR and MAPK pathway, leading to survival in absence of adhesion. More recently, Rab7 has been shown to promote EGFR/Akt signalling at late endosomes to sustain anchorage-independent growth in breast cancer cells (2). However, none of these studies definitely link the loss of adhesion with anoikis resistance, nor do they explain how integrin signalling may be reprogrammed in response to cell detachment.…”

mentioning

confidence: 99%