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

Area of Science:

• Cellular and Molecular Biology
• Immunology
• Signaling Pathways

Background:

• SHP2 (Ptpn11) is crucial for receptor tyrosine kinase-mediated RAS/ERK activation and influences PI3K/AKT signaling.
• The exact mechanisms of SHP2's differential regulation of PI3K remain incompletely understood.
• SHP2 plays a role in macrophage function and bone homeostasis.

Purpose of the Study:

• To elucidate the role of SHP2 in regulating macrophage signaling pathways, specifically in response to M-CSF.
• To investigate the mechanisms underlying SHP2's influence on PI3K/AKT activation in macrophages.
• To understand the functional consequences of SHP2 deficiency in myeloid cells.

Main Methods:

• Utilized mice with myelomonocytic cell-specific Ptpn11 deficiency (Tg(LysM-Cre); Ptpn11fl/fl).
• Analyzed bone marrow macrophages (BMMs) for proliferation, osteoclastogenesis, and signaling pathway activation (ERK, AKT).
• Employed pharmacologic inhibitors for ERK and RSK to probe signaling mechanisms.

Main Results:

• SHP2-deficient mice exhibited mild osteopetrosis.
• SHP2-deficient BMMs showed reduced proliferation and osteoclast generation in response to M-CSF.
• M-CSF-induced ERK1/2 activation was decreased, while AKT activation was enhanced in SHP2-deficient BMMs.
• An ERK/RSK2-mediated negative feedback loop was identified, negatively regulating M-CSF receptor phosphorylation and subsequent PI3K activation.
• Pharmacologic inhibition of ERK or RSK mimicked the signaling defects observed in SHP2-deficient BMMs.
• Enhanced PI3K/AKT activation in SHP2-deficient BMMs promoted cell survival.

Conclusions:

• SHP2 deficiency in macrophages disrupts M-CSF signaling, leading to impaired osteoclastogenesis.
• A novel ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.
• This feedback mechanism enhances BMM survival under conditions of SHP2 deficiency.