Dataset Information

A positive feedback loop of ARF6 activates ERK1/2 signaling pathway via DUSP6 silencing to promote pancreatic cancer progression.

ABSTRACT: ERK1/2 are essential proteins mediating mitogen-activated protein kinase signaling downstream of RAS in pancreatic adenocarcinoma (PDAC). Our previous study reveals that ARF6 plays a positive regulatory role in ERK1/2 pathway in a feedback loop manner. A significant part of the literature on ARF6 has emphasized its oncogenic effect as an essential downstream molecule of ERK1/2, and no research has been done on the regulation mechanisms of the feedback loop between ARF6 and the ERK1/2 signaling pathway. In the present study, we explore the gene network downstream of ARF6 and find that DUSP6 may be the critical signal molecule in the positive feedback loop between ARF6 and ERK1/2. Specifically, to elucidate the negative correlations between ARF6 and DUSP6 in pancreatic cancer, we examine their expressions in pancreatic cancer tissues by immunohistochemical staining. Then the impact of DUSP6 on the proliferation and apoptosis of PDAC cells are investigated by gain-of-function and loss-of-function approaches. Mechanism explorations uncover that ARF6 suppresses the expression of DUSP6, which is responsible for the dephosphorylation of ERK1/2. Altogether, these results indicate that DUSP6 plays a tumor-suppressive role and acts as an intermediate molecule between ARF6 and ERK1/2 in PDAC cells, thereby forming a positive feedback loop.

SUBMITTER: Xiao B

PROVIDER: S-EPMC9827993 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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A positive feedback loop of ARF6 activates ERK1/2 signaling pathway via <i>DUSP6</i> silencing to promote pancreatic cancer progression.

Xiao Bingkai B Zhang Yue Y Lu Zekun Z Chen Weibo W An Yong Y Zu Guangchen G Xu Xiaowu X Wu Di D Yang Hao H Qin Yi Y Chen Xuemin X

Acta biochimica et biophysica Sinica 20220801 10

ERK1/2 are essential proteins mediating mitogen-activated protein kinase signaling downstream of RAS in pancreatic adenocarcinoma (PDAC). Our previous study reveals that ARF6 plays a positive regulatory role in ERK1/2 pathway in a feedback loop manner. A significant part of the literature on ARF6 has emphasized its oncogenic effect as an essential downstream molecule of ERK1/2, and no research has been done on the regulation mechanisms of the feedback loop between ARF6 and the ERK1/2 signaling p ...[more]

PMID: 36017891

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Project description:UnlabelledEntry into cells is critical for virulence of the human bacterial pathogens Shigella spp. Shigella spp. induce membrane ruffle formation and macropinocytic uptake, but the events instigating this process are incompletely understood. The host small GTPase ADP-ribosylation factor 6 (ARF6) functions in membrane trafficking at the plasma membrane and activates membrane ruffle formation. We demonstrate that ARF6 is required for efficient Shigella flexneri entry, is activated by S. flexneri dependent on the phosphatase activity of the type III secreted effector IpgD, and depends on cytohesin guanine nucleotide exchange factors (GEFs) for recruitment to entry sites. The cytohesin GEF ARF nucleotide binding site opener (ARNO) is recruited to these sites, also dependent on IpgD phosphatase activity. ARNO recruitment is independent of ARF6, indicating that, in addition to the described recruitment of ARNO by ARF6, ARNO is recruited upstream of ARF6. Our data provide evidence that ARF6, IpgD, phosphoinositide species, and ARNO constitute a previously undescribed positive feedback loop that amplifies ARF6 activation at bacterial entry sites, thereby promoting efficient S. flexneri uptake.ImportanceShigella spp. cause diarrhea and dysentery by infection of epithelial cells in the human colon. Critical to disease is the ability of Shigella to enter into cells, yet the mechanisms involved in entry are incompletely understood. We demonstrate that the small GTPase ADP-ribosylation factor 6 (ARF6) is required for efficient cellular entry of Shigella flexneri and that activation of ARF6 depends on the phosphatase activity of the Shigella protein IpgD, which is introduced into cells via the bacterial type III secretion system. We further show that IpgD phosphatase activity is required for recruitment of the ARF6 guanine nucleotide exchange factor (GEF) ARF nucleotide binding site opener (ARNO) to bacterial entry sites and that ARNO lies upstream of ARF6 activation. These relationships define a positive feedback loop that contributes to activation of ARF6 at S. flexneri entry sites and leads to local amplification of signals that promote bacterial entry.

Dataset Information

A positive feedback loop of ARF6 activates ERK1/2 signaling pathway via DUSP6 silencing to promote pancreatic cancer progression.

Publications

A positive feedback loop of ARF6 activates ERK1/2 signaling pathway via <i>DUSP6</i> silencing to promote pancreatic cancer progression.

Similar Datasets

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