| First Author | Conner JR | Year | 2009 |
| Journal | J Exp Med | Volume | 206 |
| Issue | 7 | Pages | 1615-31 |
| PubMed ID | 19564352 | Mgi Jnum | J:150264 |
| Mgi Id | MGI:3850255 | Doi | 10.1084/jem.20090490 |
| Citation | Conner JR, et al. (2009) A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. J Exp Med 206(7):1615-31 |
| abstractText | In a phenotypic screen of the wild-derived mouse strain MOLF/Ei, we describe an earlier and more potent toll-like receptor (TLR)-mediated induction of IL-6 transcription compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the IkappaB kinase axis as well as p38, but not extracellular signal-regulated kinase or c-Jun N-terminal kinase, mitogen-activated protein kinase (MAPK) phosphorylation. The trait was mapped to the Why1 locus, which contains Irak2, a gene previously implicated as sustaining the late phase of TLR responses. In the MOLF/Ei TLR signaling network, IRAK-2 promotes early nuclear factor kappaB (NF-kappaB) activity and is essential for the activation of p38 MAPK. We identify a deletion in the MOLF/Ei promoter of the inhibitory Irak2c gene, leading to an increased ratio of pro- to antiinflammatory IRAK-2 isoforms. These findings demonstrate that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-kappaB activation in this model organism. In addition, they demonstrate that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways. |
