Negative feedback and ultrasensitivity can bring about oscillations in themitogen-activated protein kinase cascades

Functional organization of signal transduction into protein phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) cascades, gr eatly enhances the sensitivity of cellular targets to external stimuli. The sensitivity increases multiplicatively with the number of cascade levels, so that a tiny change in a stimulus results in a large change in the respon se, the phenomenon referred to as ultrasensitivity. In a variety of cell ty pes, the MAPK cascades are imbedded in long feedback loops, positive or neg ative, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. Here we demonstrate that a negative feedba ck loop combined with intrinsic ultrasensitivity of the MAPK cascade can br ing about sustained oscillations in MAPK phosphorylation. Based on recent k inetic data on the MAPK cascades, we predict that the period of oscillation s can range from minutes to hours. The phosphorylation level can vary betwe en the base level and almost 100% of the total protein. The oscillations of the phosphorylation cascades and slow protein diffusion in the cytoplasm c an lead to intracellular waves of phospho-proteins.