RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis

Zhang, Huazhi; Cui, Zhenzhong; Cheng, Du; Du, Yanyun; Guo, Xiaoli; Gao, Ru; Chen, Jianwen; Sun, Wanwei; He, Ruirui; Ma, Xiaojian; Peng, Qianwen; Martin, Bradley N.; Yan, Wei; Rong, Yueguang; Wang, Chenhui

doi:10.1080/15548627.2020.1851496

Cited by 28 publications

(20 citation statements)

References 62 publications

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“…We are in the process of examining the impact of ephrin binding on the pro-autophagic function of EphB2 in breast cancer. Interestingly, it has been shown that EphB2-ephrin-B1 interaction regulates autophagy in colonic epithelial cells [ 56 ]. It is therefore plausible that in DCIS, the interaction of EphB2 with cognate ephrin ligands could control its pro-autophagic function in mammary cells and subsequently favor its pro-apoptotic role.…”

Section: Discussionmentioning

confidence: 99%

The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

Ebrahim

Hailat

Bandyopadhyay

et al. 2021

IJMS

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Cell–cell communication proteins Eph and ephrin constitute the largest family of receptor tyrosine kinases (RTKs). They are distinguished by the fact that both receptors and ligands are membrane-bound, and both can drive intracellular signaling in their respective cells. Ever since these RTKs have been found to be involved in cancer development, strategies to target them therapeutically have been actively pursued. However, before this goal can be rationally achieved, the contributions of either Eph receptors or their ephrin ligands to cancer development and progression should be scrutinized in depth. To assess the clinical pertinence of this concern, we performed a systematic review and meta-analysis of the prognostic/predictive value of EphB2 and its multiple cognate ephrin ligands in breast cancer. We found that EphB2 has prognostic value, as indicated by the association of higher EphB2 expression levels with lower distant metastasis-free survival (DMFS), and the association of lower EphB2 expression levels with poorer relapse-free survival (RFS). We also found that higher EphB2 expression could be a prognostic factor for distant metastasis, specifically in the luminal subtypes of breast cancer. EFNB2 showed a marked correlation between higher expression levels and shorter DMFS. EFNA5 or EFNB1 overexpression is correlated with longer RFS. Increased EFNB1 expression is correlated with longer OS in lymph node (LN)-negative patients and the luminal B subtype. Higher levels of EFNB2 or EFNA5 are significantly correlated with shorter RFS, regardless of LN status. However, while this correlation with shorter RFS is true for EFNB2 in all subtypes except basal, it is also true for EFNA5 in all subtypes except HER2+. The analysis also points to possible predictive value for EphB2. In systemically treated patients who have undergone either endocrine therapy or chemotherapy, we found that higher expression of EphB2 is correlated with better rates of RFS. Bearing in mind the limitations inherent to any mRNA-based profiling method, we complemented our analysis with an immunohistochemical assessment of expression levels of both the EphB2 receptor and cognate ephrin ligands. We found that the latter are significantly more expressed in cancers than in normal tissues, and even more so in invasive and metastatic samples than in ductal carcinoma in situ (DCIS). Finally, in an in vitro cellular model of breast cancer progression, based on H-Ras-transformation of the MCF10A benign mammary cell line, we observed dramatic increases in the mRNA expression of EphB2 receptor and EFNB1 and EFNB2 ligands in transformed and invasive cells in comparison with their benign counterparts. Taken together, these data show the clinical validity of a model whereby EphB2, along with its cognate ephrin ligands, have dual anti- and pro-tumor progression effects. In so doing, they reinforce the necessity of further biological investigations into Ephs and ephrins, prior to using them in targeted therapies.

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Section: Discussionmentioning

confidence: 99%

The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

Ebrahim

Hailat

Bandyopadhyay

et al. 2021

IJMS

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“…Further, a recent study found that unresolved ER stress in intestinal epithelial cells activates the ATF6 pathway, which promotes intestinal inflammation (51). The focus of the limited reports examining functions for RNF186 has also been predominantly in epithelial cells (11)(12)(13)(14)(15)(16). Within epithelial cell lineages, a couple of reports have described a role for RNF186 in ER stress.…”

Section: Methodsmentioning

confidence: 99%

“…This was in the context of a reduced colonic UPR, reduced myeloid cell responses, reduced colonic inflammatory macrophage outcomes during intestinal injury in vivo, we utilized the DSS model of acute injury; this model allows for assessing handling of high levels of intestinal resident microbes, which we hypothesize will be impaired with RNF186 deficiency. Of note is that 2 prior studies identified increased DSS-induced disease severity with RNF186 deficiency (12,14), but the focus of these studies was on epithelial responses; they did not examine myeloid cell regulation and did not evaluate bacterial handling, which is an important determinant of intestinal injury. We first assessed the regulation of pathways in ex vivo isolated intestinal macrophages in a DSS time course; the isolated macrophages were further cocultured ex vivo with S. Typhimurium so as to examine the inducible responses in these cells.…”

Section: Rnf186 Localizes To the Er And Promotes The Nucleotide-binding Oligomerization Domain Containing 2-induced Upr In Human Macrophamentioning

confidence: 99%

“…Reports have focused on RNF186 functions mainly in epithelial cells (11)(12)(13)(14)(15)(16). RNF186-deficient mice and mice with a knockin of the rare RNF186 A64T variant demonstrate more severe dextran sodium sulfate-induced (DSS-induced) colitis associated with intestinal epithelial dysregulation (12,14). Yet another study identified a role for RNF186 in regulating nutrient sensing in epithelial cells (16).…”

Section: Introductionmentioning

confidence: 99%

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Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response

Ranjan¹,

Hedl²,

Sinha³

et al. 2021

Journal of Clinical Investigation

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“…Further mechanistic studies revealed that the ER localization of RNF186 in macrophages and its mediated ubiquitination of activating transcription factor 6 (ATF6) were crucial steps in NOD2-induced antimicrobial effect ( 108 ). In addition, increased sensitivity to DSS colitis in Rnf186 -/- mice was linked to reduced autophagy in the colonic epithelia attributed to RNF186 mediating K27-linked ubiquitination of EphB receptor B2 (EPHB2) at K892 site and further recruiting MAP1LC3B for autophagy ( 174 ). This RNF186-dependent, EPHB2-induced autophagy helped to promote the clearance of bacteria from the colonic epithelium ( 174 ).…”

Section: Ub E3 Ligases and Ibdmentioning

confidence: 99%

The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

et al. 2021

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Inflammatory bowel disease (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), exhibits a complex multifactorial pathogenesis involving genetic susceptibility, imbalance of gut microbiota, mucosal immune disorder and environmental factors. Recent studies reported associations between ubiquitination and deubiquitination and the occurrence and development of inflammatory bowel disease. Ubiquitination modification, one of the most important types of post-translational modifications, is a multi-step enzymatic process involved in the regulation of various physiological processes of cells, including cell cycle progression, cell differentiation, apoptosis, and innate and adaptive immune responses. Alterations in ubiquitination and deubiquitination can lead to various diseases, including IBD. Here, we review the role of E3 ubiquitin ligases and deubiquitinases (DUBs) and their mediated ubiquitination and deubiquitination modifications in the pathogenesis of IBD. We highlight the importance of this type of posttranslational modification in the development of inflammation, and provide guidance for the future development of targeted therapeutics in IBD.

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RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis

Cited by 28 publications

References 62 publications

The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response

The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

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