Tumour necrosis factor alpha and interleukin 1 signalling: do MAPKK kinases connect it all?

The potent pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-l) are capable of triggering biologically similar effects through activation of the same set of transcription factors. Based on recent findings it is now becoming evident that certain members of the mitogen-activated protein kinase kinase (MAPKK) kinase protein family serve to integrate the individual signal transduction pathways that are initiated by the two cytokines into an array of parallel and common signalling cascades. The link between the receptor proximal, signal-specific intracellular events and the common MAPKK kinases appears to be made by a new class of proteins known as TNF receptor associated factors (TRAFs). Here, Jorg Eder describes how TNF-alpha and IL-l use different, pathway-specific TRAFs to activate the same MAPKK kinase-controlled cascades.