Phosphatidylinositol 3-kinase is recruited to a specific site in the activated IL-1 receptor I.
Interleukin 1 (IL-1) delivers a stimulatory signal which increases the expression of a set of genes by modulating the transcription factor NF-kappaB. The IL-1 receptors are transmembrane glycoproteins which lack a catalytic domain. The C-terminal portion of the type I IL-1 receptor (IL-IRI) is essential for IL-1 signalling and for IL-1 dependent activation of NF-kappaB. This portion contains a putative phosphatidylinositol 3-kinase (PI 3-kinase) binding domain (Tyr-E-X-Met), which is highly conserved between the human, mouse and chicken sequences, as well as the related cytoplasmic domain of the Drosophila receptor Toll. This observation prompted us to investigate the role of PI 3-kinase in IL-1 signalling. Here we report evidence that PI 3-kinase is recruited by the activated IL-IRI, causing rapid and transient activation of PI 3-kinase. We also show that the receptor is tyrosine phosphorylated in response to IL-1. Expression of a receptor mutant lacking the putative binding site for p85 demonstrates that Tyr479 in the receptor cytoplasmic domain is essential for PI 3-kinase activation by IL-1. Our results indicate that PI 3-kinase is likely to be an important mediator of some IL-1 effects, providing docking sites for additional signalling molecules.
Marmiroli
S
S
Istituto di Citomorfologia Normale e Patologica del C.N.R., Bologna, Italy. marmiroli@area.bo.cnr.it
Bavelloni
A
A
Faenza
I
I
Sirri
A
A
Ognibene
A
A
Cenni
V
V
Tsukada
J
J
Koyama
Y
Y
Ruzzene
M
M
Ferri
A
A
Auron
P E
PE
Toker
A
A
Maraldi
N M
NM
D001665:Binding Sites; D016384:Consensus Sequence; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D012516:Osteosarcoma; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
D007375:Interleukin-1; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D019000:Phosphotyrosine; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases