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:
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.
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Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades.
- Kholodenko BN
- European journal of biochemistry , 3/ 2000 , Volume 267 , pages: 1583-1588 , PubMed ID: 10712587
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Boris.Kholodenko@mail.tju.edu
- 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.
Submitter of this revision: Nicolas Le Novère
Modellers: Nicolas Le Novère
Metadata information
isDescribedBy (1 statement)
hasTaxon (1 statement)
isVersionOf (1 statement)
isHomologTo (1 statement)
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SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000010_url.xml | SBML L2V4 representation of Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade | 30.83 KB | Preview | Download |
Additional files |
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| BIOMD0000000010-biopax2.owl | Auto-generated BioPAX (Level 2) | 21.58 KB | Preview | Download |
| BIOMD0000000010-biopax3.owl | Auto-generated BioPAX (Level 3) | 29.90 KB | Preview | Download |
| BIOMD0000000010.m | Auto-generated Octave file | 6.20 KB | Preview | Download |
| BIOMD0000000010.pdf | Auto-generated PDF file | 183.26 KB | Preview | Download |
| BIOMD0000000010.png | Auto-generated Reaction graph (PNG) | 59.98 KB | Preview | Download |
| BIOMD0000000010.sci | Auto-generated Scilab file | 3.78 KB | Preview | Download |
| BIOMD0000000010.svg | Auto-generated Reaction graph (SVG) | 29.90 KB | Preview | Download |
| BIOMD0000000010.vcml | Auto-generated VCML file | 42.30 KB | Preview | Download |
| BIOMD0000000010.xpp | Auto-generated XPP file | 3.79 KB | Preview | Download |
| BIOMD0000000010_manual.png | Manually generated Reaction graph (PNG) | 59.98 KB | Preview | Download |
| BIOMD0000000010_manual.svg | Manually generated Reaction graph (SVG) | 29.90 KB | Preview | Download |
| BIOMD0000000010_urn.xml | Auto-generated SBML file with URNs | 26.35 KB | Preview | Download |
- Model originally submitted by : Nicolas Le Novère
- Submitted: Sep 13, 2005 1:39:02 PM
- Last Modified: Jun 2, 2015 1:04:33 PM
Revisions
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Version: 2
- Submitted on: Jun 2, 2015 1:04:33 PM
- Submitted by: Nicolas Le Novère
- With comment: Current version of Kholodenko2000 - Ultrasensitivity and negative feedback bring oscillations in MAPK cascade
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Version: 1
- Submitted on: Sep 13, 2005 1:39:02 PM
- Submitted by: Nicolas Le Novère
- With comment: Original import of BIOMD0000000010.xml.origin
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| MAPK PP Mitogen-activated protein kinase 1 |
10.0 nmol |
| MKK P Dual specificity mitogen-activated protein kinase kinase 1 |
10.0 nmol |
| MKK PP Dual specificity mitogen-activated protein kinase kinase 1 |
10.0 nmol |
| MKK Dual specificity mitogen-activated protein kinase kinase 1 |
280.0 nmol |
| MKKK P RAF proto-oncogene serine/threonine-protein kinase |
10.0 nmol |
| MAPK P Mitogen-activated protein kinase 1 |
10.0 nmol |
| MKKK RAF proto-oncogene serine/threonine-protein kinase |
90.0 nmol |
| Reactions | Rate | Parameters |
|---|---|---|
| MAPK_P => MAPK_PP; MKK_PP | uVol*k8*MKK_PP*MAPK_P/(KK8+MAPK_P) | KK8=15.0; k8=0.025 |
| MKK_P => MKK | uVol*V6*MKK_P/(KK6+MKK_P) | V6=0.75; KK6=15.0 |
| MKK_P => MKK_PP; MKKK_P | uVol*k4*MKKK_P*MKK_P/(KK4+MKK_P) | k4=0.025; KK4=15.0 |
| MKK_PP => MKK_P | uVol*V5*MKK_PP/(KK5+MKK_PP) | V5=0.75; KK5=15.0 |
| MKKK => MKKK_P; MAPK_PP | uVol*V1*MKKK/((1+(MAPK_PP/Ki)^n)*(K1+MKKK)) | Ki=9.0; V1=2.5; K1=10.0; n=1.0 |
| MKK => MKK_P; MKKK_P | uVol*k3*MKKK_P*MKK/(KK3+MKK) | KK3=15.0; k3=0.025 |
(added: 15 Jul 2013, 13:30:51, updated: 15 Jul 2013, 13:30:51)