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CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation
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CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation
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Journal Article
CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation
2014
Overview
Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage prolifera tion is promoted by macrophage colonystimulating factor （MCSF）induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2interacting protein1 （CKIP1） as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degra dation of CKIP1. Upon MCSF stimulation, Akt is activated by CSF1RPI3K and then inactivates GSIOp, leading to the stabilization of CKIP1 and β-catenin proteins, pcatenin promotes the expression of proliferation genes in cluding cyclin D and cMyc. CKIP1 interacts with TRAF6, a ubiquitin ligase required for K631inked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6mediated Akt activation. By this means, CKIP1 inhibits macrophage proliferation specifically at the late stage after MCSF stimulation. Furthermore, CKIP1 defi ciency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1/ mice sponta neously develop a macrophagedominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Akt
/ Animals
/ Biomedical and Life Sciences
/ Bone Marrow Cells - cytology
/ Carrier Proteins - metabolism
/ Glycogen Synthase Kinase 3 - metabolism
/ Glycogen Synthase Kinase 3 beta
/ Humans
/ Macrophage Colony-Stimulating Factor - pharmacology
/ Mice
/ Original
/ Phosphatidylinositol 3-Kinases - metabolism
/ Proto-Oncogene Proteins c-akt - antagonists & inhibitors
/ Proto-Oncogene Proteins c-akt - metabolism
/ Proto-Oncogene Proteins c-myc - genetics
/ Proto-Oncogene Proteins c-myc - metabolism
/ TNF Receptor-Associated Factor 6 - antagonists & inhibitors
/ TNF Receptor-Associated Factor 6 - genetics
/ TNF Receptor-Associated Factor 6 - metabolism
/ 介导
/ 小鼠巨噬细胞
/ 激活
/ 细胞周期蛋白D
/ 细胞增殖
/ 酪蛋白激酶
