The PH domain containing protein CKIP-1 binds to IFP35 and Nmi and is involved in cytokine signaling.
The pleckstrin homology domain-containing protein CKIP-1 is implicated in regulation of cell differentiation, apoptosis, cytoskeleton as well as recruitment of CK2 and ATM kinases to plasma membrane. Protein-protein interactions of CKIP-1 were required for these functions. Here we identify the IFN-induced protein IFP35 and its homologue Nmi as two novel CKIP-1 interacting partners. The NID domains of IFP35 and Nmi are required for the interactions. Similar to IFP35 and Nmi, CKIP-1 can be up-regulated dramatically by IFN-gamma and IL-2 and form homodimer and homotrimer in vivo. Nmi stabilizes IFP35, whereas CKIP-1 destabilizes IFP35 via inhibiting IFP35-Nmi interaction. The ratio of Nmi to CKIP-1 determines the stability of IFP35 and control cytokine signaling in a novel mechanism. Importantly, similar to Nmi and contrast to IFP35, CKIP-1 inhibits tumor cell growth and Akt-mediated cell survival. Thus, our results provide a novel role of CKIP-1 in cytokine signaling response and the biochemical mechanism, by which two previously identified modulators IFP35 and Nmi are involved via interactions.
Zhang
Lingqiang
L
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing Proteomics Research Center, 27 Taiping Road, Beijing 100850, China. zhanglq@nic.bmi.ac.cn
Tang
Ying
Y
Tie
Yi
Y
Tian
Chunyan
C
Wang
Jian
J
Dong
Yan
Y
Sun
Zhixian
Z
He
Fuchu
F
D000818:Animals; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D019281:Dimerization; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation
D002352:Carrier Proteins; D018076:DNA, Complementary; C085378:IFI35 protein, human; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; C099927:NMI protein, human; C408877:PLEKHO1 protein, human; D007371:Interferon-gamma