Principles behind the multifarious control of signal transduction. ERK phosphorylation and kinase/phosphatase control

Abstract

General and simple principles are identified that govern signal transduction. The effects of kinase and phosphatase inhibition on a MAP kinase pathway are first examined in silico. Quantitative measures for the control of signal amplitude, duration and integral strength are introduced. We then identify and prove new principles, such that total control on signal amplitude and on final signal strength must amount to zero, and total control on signal duration and on integral signal intensity must equal -1. Collectively, kinases control amplitudes more than duration, whereas phosphatases tend to control both. We illustrate and validate these principles experimentally: (a) a kinase inhibitor affects the amplitude of EGF-induced ERK phosphorylation much more than its duration and (b) a phosphatase inhibitor influences both signal duration and signal amplitude, in particular long after EGF administration. Implications for the cellular decision between growth and differentiation are discussed.