Open AccessNegative feedback and ultrasensitivity can bring about oscillations in the mitogen‐activated protein kinase cascades
Author(s) -
Kholodenko Boris N.
Publication year - 2000
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2000.01197.x
Subject(s) - mapk cascade , mapk/erk pathway , phosphorylation , microbiology and biotechnology , cascade , protein kinase a , negative feedback , kinase , protein phosphorylation , mitogen activated protein kinase , biology , signal transduction , phosphorylation cascade , positive feedback , biophysics , chemistry , physics , engineering , chromatography , voltage , electrical engineering , quantum mechanics
Functional organization of signal transduction into protein phosphorylation cascades, such as the mitogen‐activated protein kinase (MAPK) cascades, greatly 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 response, the phenomenon referred to as ultrasensitivity. In a variety of cell types, the MAPK cascades are imbedded in long feedback loops, positive or negative, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. Here we demonstrate that a negative feedback loop combined with intrinsic ultrasensitivity of the MAPK cascade can bring about sustained oscillations in MAPK phosphorylation. Based on recent kinetic data on the MAPK cascades, we predict that the period of oscillations can range from minutes to hours. The phosphorylation level can vary between the base level and almost 100% of the total protein. The oscillations of the phosphorylation cascades and slow protein diffusion in the cytoplasm can lead to intracellular waves of phospho‐proteins.