Adaptor protein Lnk inhibits c-Fms-mediated macrophage function.
The M-CSFR (c-Fms) participates in proliferation, differentiation, and survival of macrophages and is involved in the regulation of distinct macrophage functions. Interaction with the ligand M-CSF results in phosphorylation of tyrosine residues on c-Fms, thereby creating binding sites for molecules containing SH2 domains. Lnk is a SH2 domain adaptor protein that negatively regulates hematopoietic cytokine receptors. Here, we show that Lnk binds to c-Fms. Biological and functional effects of this interaction were examined in macrophages from Lnk-deficient (KO) and WT mice. Clonogenic assays demonstrated an elevated number of M-CFUs in the bone marrow of Lnk KO mice. Furthermore, the M-CSF-induced phosphorylation of Akt in Lnk KO macrophages was increased and prolonged, whereas phosphorylation of Erk was diminished. Zymosan-stimulated production of ROS was increased dramatically in a M-CSF-dependent manner in Lnk KO macrophages. Lastly, Lnk inhibited M-CSF-induced migration of macrophages. In summary, we show that Lnk binds to c-Fms and can blunt M-CSF stimulation. Modulation of levels of Lnk in macrophages may provide a unique therapeutic approach to increase innate host defenses.
Gueller
Saskia
S
Department of Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany. saskia.gueller@kgu.de
Goodridge
Helen S
HS
Niebuhr
Birte
B
Xing
Hongtao
H
Koren-Michowitz
Maya
M
Serve
Hubert
H
Underhill
David M
DM
Brandts
Christian H
CH
Koeffler
H Phillip
HP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D016186:Receptor, Macrophage Colony-Stimulating Factor