Cytosolic double-stranded DNA (dsDNA) triggers type-I interferon production through the endoplasmic reticulum adaptor protein STING (also known as MITA, MPYS and ERIS), which activates the transcription factor IRF3. However, how STING activates IRF3 remains largely unknown. Here we show that STING stimulates IRF3 phosphorylation by the kinase TBK1 in an in vitro reconstitution system. Using this system, we identified a carboxyl terminal region of STING that is both necessary and sufficient to activate TBK1 and stimulate IRF3 phosphorylation. Interestingly, we found that STING interacts with both TBK1 and IRF3, and that mutations in STING that selectively disrupt its binding to IRF3 abrogate IRF3 phosphorylation without impairing TBK1 activation. These results suggest that STING functions as a scaffold to specify and promote IRF3 phosphorylation by TBK1. The scaffolding function of STING and other adaptors may explain why IRF3 is activated only in a subset of signaling pathways that activate TBK1.
Sarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC.
Mutations in the PIK3CA gene, which encodes the p110A catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not been examined. In this study, we examined the effects of colon cancer-associated PIK3CA mutations on the lipid kinase activity in vitro, activation of the downstream targets Akt and p70S6K in vivo and NIH 3T3-transforming ability. Of eight mutations examined, all showed increased lipid kinase activity compared with wild-type p110A. All the mutants strongly activated Akt and p70S6K compared with wild-type p110A as determined by immunoblotting using phospho-specific antibodies. These mutants also induced morphologic changes, loss of contact inhibition, and anchorage-independent growth of NIH 3T3 cells. The hotspot mutations examined in this study, E542K, E545K, and H1047R, all had high enzymatic and transforming activities. These results show that almost all the colon cancer-associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis. (Cancer Res 2005; 65(11): 4562-7)
Round the twist: Metalation of [36]octaphyrin 1 provided the Möbius aromatic Pd2 complex 3 as well as the Hückel antiaromatic Pd2 complex 2. This method can be applied to other expanded porphyrins and Group 10 metal ions. The aromatic/antiaromatic character was supported by NMR spectrscopy, NICS calculation, and two‐photon absorption measurements.
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