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

• Type of Material: Article
• Authors: Lijun Wang, Brown University; Caterina Iorio, University of Toronto; Kevin Yan, Brown University; Howard Yang, University of Rhode Island; Sunao Takeshita, NationalCenter for Geriatrics and Gerontology; Su Kang, Emory University; Benjamin G. Neel, University of Toronto; Wentian Yang, Brown University
• Language: English
• Date: 2017-10-18
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: © FASEB
• Final Published Version (URL): http://www.fasebj.org/content/early/2017/10/18/fj.201700672RR
• Title of Journal or Parent Work: FASEB Journal
• ISSN: 0892-6638
• Grant/Funding Information: This work was supported in part by NIH grants R01CA114945 and R37 CA49152 (B.G.N.), R21AR57156, RO1AR066746 and P20RR025179 (W.Y.).; This study was also aided by a grant from Arthritis National Research Foundation (W.Y.). B.G.N. was a Canada Research Chair, Tier 1, and this research was also funded in part by the Ontario Ministry of Health and Long Term Care.
• Keywords: MAPK; AKT; c-Fms; M-CSFR; SHP2
• Research Categories: Health Sciences, Oncology; Health Sciences, General

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);Ptpn11fl/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.