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A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

ABSTRACT: Activation of the RAS/ERK and its downstream signaling components is essential for growth factor-induced cell survival, proliferation, and differentiation. The Src homology-2 domain containing protein tyrosine phosphatase 2 (SHP2), encoded by protein tyrosine phosphatase, non-receptor type 11 ( Ptpn11), is a positive mediator required for most, if not all, receptor tyrosine kinase-evoked RAS/ERK activation, but differentially regulates the PI3K/AKT signaling cascade in various cellular contexts. The precise mechanisms underlying the differential effects of SHP2 deficiency on the PI3K pathway remain unclear. We found that mice with myelomonocytic cell-specific [ Tg(LysM-Cre); Ptpn11^fl/fl mice] Ptpn11 deficiency exhibit mild osteopetrosis. SHP2-deficient bone marrow macrophages (BMMs) showed decreased proliferation in response to M-CSF and decreased osteoclast generation. M-CSF-evoked ERK1/2 activation was decreased, whereas AKT activation was enhanced in SHP2-deficient BMMs. ERK1/2, via its downstream target RSK2, mediates this negative feedback by negatively regulating phosphorylation of M-CSF receptor at Tyr721 and, consequently, its binding to p85 subunit of PI3K and PI3K activation. Pharmacologic inhibition of RSK or ERK phenotypically mimics the signaling defects observed in SHP2-deficient BMMs. Furthermore, this increase in PI3K/AKT activation enables BMM survival in the setting of SHP2 deficiency.-Wang, L., Iorio, C., Yan, K., Yang, H., Takeshita, S., Kang, S., Neel, B.G., Yang, W. An ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

SUBMITTER: Wang L

PROVIDER: S-EPMC5888401 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

Wang Lijun L Iorio Caterina C Yan Kevin K Yang Howard H Takeshita Sunao S Kang Sumin S Neel Benjamin G BG Yang Wentian W

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180104 2

Activation of the RAS/ERK and its downstream signaling components is essential for growth factor-induced cell survival, proliferation, and differentiation. The Src homology-2 domain containing protein tyrosine phosphatase 2 (SHP2), encoded by protein tyrosine phosphatase, non-receptor type 11 ( Ptpn11), is a positive mediator required for most, if not all, receptor tyrosine kinase-evoked RAS/ERK activation, but differentially regulates the PI3K/AKT signaling cascade in various cellular contexts. ...[more]

PMID: 29046360

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Project description:BackgroundAs novel biomarkers for various cancers, microRNAs negatively regulate genes expression via promoting mRNA degradation and suppressing mRNA translation. miR-589 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in gastric cancer. Here, we aim to investigate the biological effect of miR-589 on gastric cancer and to reveal the possible mechanism.MethodsReal-time PCR was performed to evaluate the expression of miR-589 in 34 paired normal and stomach tumor specimens, as well as gastric cell lines. Functional assays, such as wound healing, transwell assays and in vivo assays, were used to detect the biological effect of miR-589 and LIFR. We determined the role of miR-589 in gastric cancer tumorigenesis in vivo using xenograft nude models. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were performed for target evaluation, and the relationships were confirmed by western blot assay.ResultMiR-589 expression was significantly higher in tumor tissues and gastric cancer cells than those in matched normal tissues and gastric epithelial cells, respectively. Clinically, overexpression of miR-589 is associated with tumor metastasis, invasion and poor prognosis of GC patients. Gain- and loss-of function experiments showed that miR-589 promoted cell migration, metastasis and invasion in vitro and lung metastasis in vivo. Mechanistically, we found that miR-589 directly targeted LIFR to activate PI3K/AKT/c-Jun signaling. Meanwhile, c-Jun bound to the promoter region of miR-589 and activated its transcription. Thus miR-589 regulated its expression in a feedback loop that promoted cell migration, metastasis and invasion.ConclusionOur study identified miR-589, as an oncogene, markedly induced cell metastasis and invasion via an atypical miR-589-LIFR-PI3K/AKT-c-Jun feedback loop, which suggested miR-589 as a potential biomarker and/or therapeutic target for the gastric cancer management.

Dataset Information

A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

Publications

A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

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