21700900

pubmed:Citation

3

To determine the impact of B cell leukemia/lymphoma (BCL) 10 on the phosphorylation of crucial mediators in NF-?B-mediated inflammatory pathways, human colonic epithelial cells were exposed to carrageenan (CGN), a sulfated polysaccharide commonly used as a food additive and known to induce NF-?B nuclear translocation by both canonical and noncanonical pathways. Phosphorylations of intermediates in inflammatory cascades, including NF-?B-inducing kinase (NIK) at Thr(559), transforming growth factor-?-activating kinase (TAK) 1 at Thr(184), Thr(187), and Ser(192), and inhibitory factor ?B? (I?B?) at Ser(32), were examined following mutation of BCL10 at Ser(138) and at Ser(218). Specific phosphoantibodies were used for detection by enzyme-linked immunosorbent assay, immunoblot, and confocal microscopy of differences in phosphorylation following transfection by mutated BCL10. Both mutations demonstrated dominant-negative effects, with inhibition of phospho(Ser(32))-I?B? to less than control levels. Both of the BCL10 mutations reduced the CGN-induced increases in nuclear RelA and p50, but only the Ser(138) mutation inhibited the CGN-induced increases in nuclear RelB and p52 and in NIK Thr(559) phosphorylation. Hence, the phosphorylation of BCL10 Ser(138), but not Ser(218), emerged as a critical event in activation of the noncanonical pathway of NF-?B activation. Either BCL10 Ser(138) or Ser(218) mutation inhibited the phosphorylation of TAK1 at Thr(184) and at Thr(187), but not at Ser(192). These findings indicate that BCL10 phosphorylations act upstream of phosphorylations of NIK, TAK1, and I?B? and differentially affect the canonical and noncanonical pathways of NF-?B activation.

eng

IM

MEDLINE

1522-1547

Electronic

NLM

G475-86

pubmed-meshheading:21700900-Adaptor Proteins, Signal Transducing, pubmed-meshheading:21700900-Benzylamines, pubmed-meshheading:21700900-Calcium-Calmodulin-Dependent Protein Kinases, pubmed-meshheading:21700900-Carrageenan, pubmed-meshheading:21700900-Cell Line, pubmed-meshheading:21700900-Colon, pubmed-meshheading:21700900-Epithelial Cells, pubmed-meshheading:21700900-Humans, pubmed-meshheading:21700900-I-kappa B Kinase, pubmed-meshheading:21700900-MAP Kinase Kinase Kinases, pubmed-meshheading:21700900-Male, pubmed-meshheading:21700900-Microscopy, Confocal, pubmed-meshheading:21700900-Middle Aged, pubmed-meshheading:21700900-NF-kappa B, pubmed-meshheading:21700900-Phosphorylation, pubmed-meshheading:21700900-Serine, pubmed-meshheading:21700900-Signal Transduction, pubmed-meshheading:21700900-Sulfonamides

Specific effects of BCL10 Serine mutations on phosphorylations in canonical and noncanonical pathways of NF-?B activation following carrageenan.

Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural