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A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.

Wang, Hui; Flannery, Sinead M; Dickhöfer, Sabine; Huhn, Stefanie; George, Julie; Kubarenko, Andriy V; Lascorz, Jesus; Bevier, Melanie LU ; Willemsen, Joschka and Pichulik, Tica, et al. (2014) In Journal of Biological Chemistry 289(33). p.23123-23131
Abstract
Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas human IRAK4-deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and TLR-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups and our studies uncovered a significant genetic association... (More)
Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas human IRAK4-deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and TLR-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups and our studies uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point. (Less)
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Contribution to journal
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published
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Journal of Biological Chemistry
volume
289
issue
33
pages
23123 - 23131
publisher
ASBMB
external identifiers
  • pmid:24973222
  • wos:000341017200049
  • scopus:84905981869
ISSN
1083-351X
DOI
10.1074/jbc.M113.492934
language
English
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yes
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18c52331-d4ae-4ccc-8ce9-1dc8bb8463e6 (old id 4523718)
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http://www.ncbi.nlm.nih.gov/pubmed/24973222?dopt=Abstract
date added to LUP
2014-07-08 11:32:08
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2017-07-09 03:14:38
@article{18c52331-d4ae-4ccc-8ce9-1dc8bb8463e6,
  abstract     = {Within innate immune signaling pathways, Interleukin-1 receptor (IL-1R&)-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors (TLR) and the IL-1R. Whereas human IRAK4-deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and TLR-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups and our studies uncovered a significant genetic association of rs35060588 with colorectal cancer survival. This for the first time firmly implicates human IRAK2 in human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.},
  author       = {Wang, Hui and Flannery, Sinead M and Dickhöfer, Sabine and Huhn, Stefanie and George, Julie and Kubarenko, Andriy V and Lascorz, Jesus and Bevier, Melanie and Willemsen, Joschka and Pichulik, Tica and Schafmayer, Clemens and Binder, Marco and Manoury, Benedicte and Paludan, Søren R and Alarcon Riquelme, Marta and Bowie, Andrew G and Försti, Asta and Weber, Alexander N R},
  issn         = {1083-351X},
  language     = {eng},
  number       = {33},
  pages        = {23123--23131},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival.},
  url          = {http://dx.doi.org/10.1074/jbc.M113.492934},
  volume       = {289},
  year         = {2014},
}