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Huang1996 - Ultrasensitivity in MAPK cascade

ABSTRACT: Huang1996 - Ultrasensitivity in MAPK cascade The temporal sequence of kinase activation, from MAPKKK (activated RAF) to the final effector MAPK (activated ERK), is described here. It is observed from the model that there is an increase in sensitivity along the levels of the cascade, where the activity of MAPK reaches its maximal before MAPKKK. This model is described in the article: Ultrasensitivity in the mitogen-activated protein kinase cascade. Huang CY, Ferrell JE Jr Proc. Natl. Acad. Sci. U.S.A. 1996:93(19):10078-83 Abstract: The mitogen-activated protein kinase (MAPK) cascade is a highly conserved series of three protein kinases implicated in diverse biological processes. Here we demonstrate that the cascade arrangement has unexpected consequences for the dynamics of MAPK signaling. We solved the rate equations for the cascade numerically and found that MAPK is predicted to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperatively. Measurements of MAPK activation in Xenopus oocyte extracts confirmed this prediction. The stimulus/response curve of the MAPK was found to be as steep as that of a cooperative enzyme with a Hill coefficient of 4-5, well in excess of that of the classical allosteric protein hemoglobin. The shape of the MAPK stimulus/ response curve may make the cascade particularly appropriate for mediating processes like mitogenesis, cell fate induction, and oocyte maturation, where a cell switches from one discrete state to another. The species K_PP_norm, KKK_P_norm and KK_PP_norm are the relative concentrations of the active MAPK, MAPKK and MAPKKK, that is the double, or single resp. phophorylated forms divided by the total concentrations of each kinase. For MAPK additionally the also active MAPK divided by the maximal concentration of active MAPK is given by rel_K_PP_max. The parameter K_PP_norm_max, the maximal ratio of active MapK, has to be calculated for each change of parameters. This model is hosted on BioModels Database and identified by: BIOMD0000000009 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Nicolas Le Novère

PROVIDER: BIOMD0000000009 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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Ultrasensitivity in the mitogen-activated protein kinase cascade.

Huang C Y CY Ferrell J E JE

Proceedings of the National Academy of Sciences of the United States of America 19960901 19

The mitogen-activated protein kinase (MAPK) cascade is a highly conserved series of three protein kinases implicated in diverse biological processes. Here we demonstrate that the cascade arrangement has unexpected consequences for the dynamics of MAPK signaling. We solved the rate equations for the cascade numerically and found that MAPK is predicted to behave like a highly cooperative enzyme, even though it was not assumed that any of the enzymes in the cascade were regulated cooperatively. Mea ...[more]

PMID: 8816754

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Project description:Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade The combination of ultrasensitivity and negative feedback bring sustained oscillations in the mitogen-activated protein kinase cascades. This model is described in the article: Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Kholodenko BN Eur. J. Biochem. 2000; 267(6):1583-8 Abstract: 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. This model is hosted on BioModels Database and identified by: BIOMD0000000010 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.