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PMID:16751103

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Citation

Kagan, JC and Medzhitov, R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125:943-55

Abstract

Toll-like receptors (TLRs) play a critical role in the immune system as sensors of microbial infection. Signaling downstream from TLRs is initiated by the recruitment of adaptor proteins, including MyD88 and TIRAP. These adaptors play essential roles in TLR signaling, but the mechanism of their function is currently unknown. Here we demonstrate that TIRAP and MyD88 have distinct functions and describe a mechanism of recruitment of TIRAP and MyD88 to TLR4. We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. These results establish that phosphoinositide-mediated adaptor recruitment initiates a specific signal-transduction pathway.

Links

PubMed Online version:10.1016/j.cell.2006.03.047

Keywords

ADP-Ribosylation Factors/metabolism; Adaptor Proteins, Signal Transducing/metabolism; Animals; Binding Sites/physiology; CHO Cells; Cell Line; Cells, Cultured; Cricetinae; Humans; Integrins/metabolism; Membrane Glycoproteins/metabolism; Membrane Lipids/metabolism; Mice; Models, Molecular; Myeloid Differentiation Factor 88; Phosphatidylinositol 4,5-Diphosphate/metabolism; Protein Binding/physiology; Protein Structure, Tertiary/physiology; Protein Transport/physiology; Receptor Cross-Talk/physiology; Receptors, Interleukin-1/metabolism; Signal Transduction/physiology; Toll-Like Receptor 4/metabolism; Toll-Like Receptors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MYD88

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MYD88

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ARF6

enables

GO:0005525: GTP binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ARF6

involved_in

GO:0034394: protein localization to cell surface

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARF6

involved_in

GO:0034143: regulation of toll-like receptor 4 signaling pathway

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARF6

enables

GO:0003924: GTPase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ARF6

located_in

GO:0005768: endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ARF6

involved_in

GO:1903078: positive regulation of protein localization to plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TIRAP

enables

GO:0005546: phosphatidylinositol-4,5-bisphosphate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:TIRAP

located_in

GO:0032587: ruffle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TIRAP

located_in

GO:0030139: endocytic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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