期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 277, 期 35, 页码 31871-31876出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M202222200
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资金
- NCI NIH HHS [F23-CA88470-01, CA84064] Funding Source: Medline
- NHLBI NIH HHS [T32-HL07622] Funding Source: Medline
- NIGMS NIH HHS [GM60421] Funding Source: Medline
Protein kinase C-associated kinase (PKK) is a recently described kinase of unknown function that was identified on the basis of its specific interaction with PKCbeta. PKK contains N-terminal kinase and C-terminal ankyrin repeats domains linked to an intermediate region. Here we report that the kinase domain of PKK is highly homologous to that of two mediators of nuclear factor-kappaB (NF-kappaB) activation, RICK and RIP, but these related kinases have different C-terminal domains for binding to upstream factors. We find that expression of PKK, like RICK and RIP, induces NF-kappaB activation. Mutational analysis revealed that the kinase domain of PKK is essential for NF-kappaB activation, whereas replacement of serine residues in the putative activation loop did not affect the ability of PKK to activate NF-kappaB. A catalytic inactive PKK mutant inhibited NF-kappaB activation induced by phorbol ester and Ca2+-ionophore, but it did not block that mediated by tumor necrosis factor alpha, interleukin-1beta, or Nod1. Inhibition of NF-kappaB activation by dominant negative PKK was reverted by co-expression of PKCbetaI, suggesting a functional association between PKK and PKCbetaI. PKK-mediated NF-kappaB activation required IKKalpha and IKKbeta but not IKKgamma, the regulatory subunit of the IKK complex. Moreover, NF-kappaB activation induced by PKK was not inhibited by dominant negative Bimp1. and proceeded in the absence of Bcl10, two components of a recently described PKC signaling pathway. These results suggest that PKK is a member of the RICK/RIP family of kinases, which is involved in a PKC-activated NF-kappaB signaling pathway that is independent of Bcl10 and IKKgamma.
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