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FASEB J. 2018 Feb;32(2):875-887. doi: 10.1096/fj.201700672RR. Epub 2018 Jan 4.

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

Author information

1
Department of Orthopaedics, Brown University Alpert Medical School, Rhode Island Hospital, Providence, Rhode Island, USA.
2
Department of Medical Biophysics, Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
3
College of Engineering, University of Rhode Island, Kingston, Rhode Island, USA.
4
Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Aichi, Japan.
5
Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
6
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York University, New York, New York, USA.

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.

KEYWORDS:

M-CSFR; MAPK; SHP2; c-Fms

PMID:
29046360
PMCID:
PMC5888401
DOI:
10.1096/fj.201700672RR
[Indexed for MEDLINE]
Free PMC Article

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