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IRAK4 — TLR4
Pathways - manually collected, often from reviews:
-
NCI Pathway Database Endogenous TLR signaling:
IRAK2 (IRAK2)
→
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP/IRAK/IRAK2/IRAK4 complex (TLR4-LY96-HMGB1-IRAK1-IRAK2-IRAK4-MYD88-TIRAP)
(modification, collaborate)
Park et al., J Biol Chem 2004
Evidence: mutant phenotype, other species
-
NCI Pathway Database Endogenous TLR signaling:
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP complex (TLR4-LY96-HMGB1-MYD88-TIRAP)
→
IRAK4 (IRAK4)
(modification, collaborate)
Park et al., J Biol Chem 2004
Evidence: mutant phenotype, other species
-
NCI Pathway Database Endogenous TLR signaling:
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP complex (TLR4-LY96-HMGB1-MYD88-TIRAP)
→
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP/IRAK/IRAK2/IRAK4 complex (TLR4-LY96-HMGB1-IRAK1-IRAK2-IRAK4-MYD88-TIRAP)
(modification, collaborate)
Park et al., J Biol Chem 2004
Evidence: mutant phenotype, other species
-
NCI Pathway Database Endogenous TLR signaling:
IRAK4 (IRAK4)
→
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP/IRAK/IRAK2/IRAK4 complex (TLR4-LY96-HMGB1-IRAK1-IRAK2-IRAK4-MYD88-TIRAP)
(modification, collaborate)
Park et al., J Biol Chem 2004
Evidence: mutant phenotype, other species
-
NCI Pathway Database Endogenous TLR signaling:
IRAK (IRAK1)
→
HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP/IRAK/IRAK2/IRAK4 complex (TLR4-LY96-HMGB1-IRAK1-IRAK2-IRAK4-MYD88-TIRAP)
(modification, collaborate)
Park et al., J Biol Chem 2004
Evidence: mutant phenotype, other species
-
Reactome Reaction:
TLR4
→
IRAK4
(reaction)
Li et al., Proc Natl Acad Sci U S A 2002, Suzuki et al., Trends Immunol 2002, Kollewe et al., J Biol Chem 2004, Cheng et al., Biochem Biophys Res Commun 2007, Kawagoe et al., J Exp Med 2007, Kawagoe et al., Nat Immunol 2008, Moncrieffe et al., J Biol Chem 2008*, Towb et al., J Innate Immun 2009*, Motshwene et al., J Biol Chem 2009, Lin et al., Nature 2010
-
Reactome Reaction:
TLR4
→
IRAK4
(indirect_complex)
Li et al., Proc Natl Acad Sci U S A 2002, Suzuki et al., Trends Immunol 2002, Cheng et al., Biochem Biophys Res Commun 2007, Kawagoe et al., J Exp Med 2007, Moncrieffe et al., J Biol Chem 2008*, Towb et al., J Innate Immun 2009*, Motshwene et al., J Biol Chem 2009, Lin et al., Nature 2010
-
WikiPathways TLR4 Signaling and Tolerance:
Complex of TIRAP-MAL-TRAM1-TLR4
→
Complex of IRAK1-MYD88-IRAK4
(activation)
Protein-Protein interactions - manually collected from original source literature:
Studies that report less than 10 interactions are marked with *
Text-mined interactions from Literome
Kobayashi et al., Cell 2002
(Salmonella Infections) :
Thus,
IRAK-M regulates
TLR signaling and innate immune homeostasis
Hazeki et al., Eur J Immunol 2003
:
PP2, an inhibitor of Src family tyrosine kinases, prevented the TLR induced phosphorylation of paxillin and Pyk2 without affecting
TLR induced
IRAK activation
Hatao et al., J Leukoc Biol 2004
:
We found that stimulation of TLR2,
TLR4 , or TLR9, but not TLR3,
caused a decrease in
IRAK-4 protein without affecting its mRNA level in a mouse macrophage cell line, RAW 264
Cuschieri et al., J Surg Res 2004
:
LPS stimulation led to the mobilization of
TLR4 to lipid rafts followed by phosphorylation and
activation of
IRAK , ERK 1/2, p38, and JNK/SAPK
Zhang et al., Infect Immun 2005
(Pseudomonas Infections) :
We also determined that MyD88,
IRAK , TRAF6, and Toll interacting protein (Tollip), but not TIRAP, were involved in the
TLR mediated response to P. aeruginosa in HAECs
Hatao et al., FEMS Immunol Med Microbiol 2008
:
IRAK-4 plays an essential role in
Toll-like receptor ( TLR ) /IL-1 receptor signaling
Koziczak-Holbro et al., Ernst Schering Foundation symposium proceedings 2007
:
In summary, our results suggest that
IRAK-4 kinase activity
plays a critical role in IL-1R-,
TLR4- , and TLR7 mediated induction of inflammatory responses
Singh et al., J Immunol 2009
(Common Variable Immunodeficiency) :
We observed impaired O ( 2 ) ( ) generation by LPS treated and fMLP activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that
TLR4 signaling to the NOX activation pathway
requires IRAK4
Staschke et al., J Immunol 2009
(Encephalomyelitis, Autoimmune, Experimental) :
The
IL-1R associated kinase 4 (IRAK4) is
critical for
IL-1/TLR signaling
Gao et al., Crit Care Med 2012
(Sepsis) :
CLP-activation of
TLR4 mediated nuclear factor-?B and
Toll/IL-1 receptor-domain containing adapter inducing interferon-ß-dependant interferon signaling pathways was prevented by TLR3 deficiency
Pennini et al., J Immunol 2013
(Genetic Predisposition to Disease...) :
IRAK4 is
critical for MyD88 dependent
TLR signaling, and patients with Irak4 mutations are extremely susceptible to recurrent bacterial infections ... Importantly, we identified two kinases downstream of the MAPKs, MNK1 and MSK1, whose phosphorylation is deficient in IRAK4 ( KDKI ) macrophages stimulated through either TLR2 or TLR4, suggesting that
IRAK4 contributes to
TLR signaling beyond the initial phosphorylation of MAPKs
von Bernuth et al., Eur J Immunol 2012
(Bacterial Infections...) :
By contrast, human
TLR- and IL-1R dependent immunity
mediated by MyD88 and
IRAK-4 seems to be effective in the natural setting against only a few bacteria and is most important in infancy and early childhood
Sandig et al., Eur J Immunol 2013
:
We show that while IRAK2 is redundant for TLR4 signaling,
IRAK1 is
essential for
TLR4 signaling in mast cells