| First Author | Patial S | Year | 2009 |
| Journal | Biochem J | Volume | 425 |
| Issue | 1 | Pages | 169-78 |
| PubMed ID | 19796012 | Mgi Jnum | J:161689 |
| Mgi Id | MGI:4460867 | Doi | 10.1042/BJ20090908 |
| Citation | Patial S, et al. (2010) G-protein-coupled-receptor kinases mediate TNFalpha-induced NF-kappaB signalling via direct interaction with and phosphorylation of IkappaBalpha. Biochem J 425(1):169-78 |
| abstractText | TNFalpha (tumour necrosis factor alpha) is a multifunctional cytokine involved in the pathophysiology of many chronic inflammatory diseases. TNFalpha activation of the NF-kappaB (nuclear factor kappaB) signalling pathway particularly in macrophages has been implicated in many diseases. We demonstrate in the present study that GRK2 and GRK5 (G-protein-coupled-receptor kinases 2 and 5) regulate TNFalpha-induced NF-kappaB signalling in Raw 264.7 macrophages. RNAi (RNA interference) knockdown of GRK2 or GRK5 in macrophages significantly inhibited TNFalpha-induced IkappaBalpha (inhibitory kappaBalpha) phosphorylation and degradation, NF-kappaB activation and expression of the NF-kappaB-regulated gene MIP1beta (macrophage inflammatory protein 1beta). Consistent with these results, overexpression of GRK2 or GRK5 enhanced TNFalpha-induced NF-kappaB activity. In addition, we show that GRK2 and GRK5 interacted with IkappaBalpha via the N-terminal domain of IkappaBalpha and that IkappaBalpha is a substrate for GRK2 and GRK5 in vitro. Furthermore, we also found that GRK5, but not GRK2, phosphorylated IkappaBalpha at the same amino acid residues (Ser32/Ser36) as that of IKKbeta (IkappaB kinase beta). Interestingly, associated with these results, knockdown of IKKbeta in Raw 264.7 macrophages did not affect TNFalpha-induced IkappaBalpha phosphorylation. Taken together, these results demonstrate that both GRK2 and GRK5 are important and novel mediators of a non-traditional IkappaBalpha/NF-kappaB signalling pathway. |
