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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.

OBJECTIVE To confirm the role played by AKT1 and AKT2 in the b-catenin/Tcf-4 signaling pathway in promoting malignant transfor-mation of glioma cells.METHODS LN229 cells were divided into five groups: a control group, acetone (ACE)group, acetylsalicylic acid (ASA; aspirin) group, ASA+AKT1 plasmid group and ASA+AKT2 plasmid group. Western blot and PCR were used to detect the expression of AKT1 and AKT2 after dealing with ASA and transferring AKT1/2 genes into LN229 cells. Cell proliferation was determined by flow cytometry, cell invasion was evaluated by transwell assay and cell apoptosis was detected with annexin V staining. The molecules regulating proliferation and invasion were examined by western blot analysis.RESULTS Aspirin down-regulates AKT1 and AKT2 expression by modulating b-catenin/Tcf-4 activity. AKT1 and AKT2 can enhance cell proliferation and invasion by up-regulating the expression of cyclin-D and matrix metalloprotein-9 (MMP-9) in LN229 glioma cells.CONCLUSION AKT1 and AKT2 play an important role in the b- catenin/Tcf-4 signaling pathway promoting malignant transformation; AKT1 is more effective than AKT2. AKT1 and AKT2 may be potential targets for brain glioma therapy and an effective way to prevent metastasis of gliomas.