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 N F-kappa B, The IL-1 receptors are transmembrane glycoproteins which la ck a catalytic domain. The C-terminal portion of the type I IL-1 recep tor (IL-1RI) is essential for IL-1 signalling and for IL-1 dependent a ctivation of NF-kappa B. This portion contains a putative phosphatidyl inositol 3-kinase (PI 3-kinase) binding domain (Tyr-E-X-Met), which is highly conserved between the human, mouse and chicken sequences, as w ell as the related cytoplasmic domain of the Drosophila receptor Toll. This observation prompted us to investigate the role of PI 3-kinase i n IL-1 signalling, Here we report evidence that PI 3-kinase is recruit ed by the activated IL-1RI, 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 puta tive binding site for p85 demonstrates that Tyr(479) in the receptor c ytoplasmic domain is essential for PI 3-kinase activation by IL-1. Our results indicate that PI 3-kinase is likely to be an important mediat or of some IL-1 effects, providing docking sites for additional signal ling molecules. (C) 1998 Federation of European Biochemical Societies.