Journal
FASEB JOURNAL
Volume 32, Issue 2, Pages 875-887Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700672RR
Keywords
SHP2; MAPK; c-Fms; M-CSFR
Categories
Funding
- U.S. National Institutes of Health (NIH) National Cancer Institute [R01CA114945, R37 CA49152]
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [R21AR57156, RO1AR066746]
- NIH National Center for Research Resources Grant [P20RR025179]
- Arthritis National Research Foundation
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Grants-in-Aid for Scientific Research [16K08681] Funding Source: KAKEN
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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.
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