LOGICAL ANALYSIS OF TIMING-DEPENDENT RECEPTOR SIGNALING SPECIFICITY -APPLICATION TO THE INSULIN-RECEPTOR METABOLIC AND MITOGENIC SIGNALINGPATHWAYS

We present a method for logical analysis of signal-transduction networ ks, focusing on metabolic and mitogenic signalling by the insulin rece ptor, with specific emphasis on dependence of the signalling propertie s on the timing of binding events. We discuss a basic model which demo nstrates this dependence (hormone binding leads to activation of the r eceptor which can lead to a commitment to mitogenic signalling), and s how how residence time of the hormone on the receptor can determine th e specificity of signalling between the alternative metabolic or mitog enic pathways. The method gives conditions for the selection of specif ic branches in the signalling pathway expressed in terms of inequaliti es among the characteristic activation or deactivation times of compon ents of that pathway. In this way, the conditions for mitogenic signal ling can be given in terms of a required range of values of the hormon e residence time on the receptor, which is directly related to the kin etic dissociation rate.