THE INVOLVEMENT OF PROTEIN PHOSPHORYLATION IN TUMOUR NECROSIS FACTOR/INTERLEUKIN-1 SIGNAL TRANSDUCTION

Abstract

The role and regulation of protein phosphorylation in Interleukin-1 and TNF signal transduction pathway was studied. Although much is known of the chemical nature of TNFs and IL-1s and the many biological responses they elicit, the signalling mechanism(s) by which they bring about these biological responses are not well understood. A study was carried out to elucidate the signal transduction pathway(s) of these cytokines. It was found that both cytokines induce changes in early protein phosphorylation in primary fibroblasts. High resolution two-dimensional gel electrophoresis was used to investigate TNF/IL-1- induced changes in tyrosine phosphorylation of fibroblast proteins. Rapid phosphorylation of a family of pp42 kD proteins was found. It was demonstrated this family of proteins could be due to the activation of MAP kinase was activated by using a praline-rich peptide substrate, a sequence found in the EGF receptor. The activation of MAP kinase was transient and rapid. This rapid activation of the enzyme was accompanied by EGF receptor phosphorylation and S6 kinase phosphorylation. In addition, 5 other cytosolic tyrosine-phosphorylated proteins (pp61,47.5,44, 39 kDa) were found to be phosphorylated using antibodies against phosphotyrosine which demonstrate that tyrosine phosphorylation may have a role to play in TNF/IL-1 signal transduction. The identification of MAP kinase activation pathway as a possible mechanism in TNF/IL-1 action has contributed to an understanding of some of the earlier cellular events which may be critical steps in the TNF/IL-1 signal transduction pathway.