Related Experiment Video

Updated: Aug 8, 2026

Temporal Quantification of MAPK Induced Expression in Single Yeast Cells
07:59

Temporal Quantification of MAPK Induced Expression in Single Yeast Cells

Published on: October 5, 2013

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

B N Kholodenko1

  • 1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Boris.Kholodenko@mail.tju.edu

European Journal of Biochemistry
|March 11, 2000
PubMed

Insights

Mitogen-activated protein kinase (MAPK) cascades, when ultrasensitive and coupled with negative feedback, can generate sustained oscillations in cell signaling. These dynamics may lead to intracellular waves of phospho-proteins.

Area of Science:

  • Cellular signaling dynamics
  • Biophysics of signal transduction

Background:

  • Protein phosphorylation cascades, like MAPK, amplify external stimuli, exhibiting ultrasensitivity.
  • MAPK cascades often incorporate feedback loops (positive or negative) influencing cellular responses.

Purpose of the Study:

  • To investigate if negative feedback and ultrasensitivity in MAPK cascades can induce sustained oscillations.
  • To predict the characteristics and potential consequences of these oscillations.

Main Methods:

  • Mathematical modeling and kinetic analysis of MAPK cascade signaling pathways.
  • Integration of ultrasensitivity principles with negative feedback loop dynamics.

Main Results:

  • Demonstrated that negative feedback combined with MAPK ultrasensitivity drives sustained oscillations in phosphorylation.
  • Predicted oscillation periods from minutes to hours, with phosphorylation levels varying widely.
  • Linked oscillations and protein diffusion to the formation of intracellular phospho-protein waves.

Conclusions:

  • Negative feedback is crucial for generating oscillatory behavior in ultrasensitive MAPK cascades.
  • These oscillations and diffusion dynamics can create propagating waves within cells.
  • The findings offer insights into complex cellular responses and signal processing.

More Related Videos

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development09:32

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

Published on: June 15, 2017

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Related Concept Videos

Intracellular Signaling Cascades01:24

Intracellular Signaling Cascades

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
Cell Signaling Feedback Loops01:07

Cell Signaling Feedback Loops

Positive and negative feedback loops are crucial for regulating biological signaling systems. These feedback loops are processes that connect output signals to their inputs.
Negative feedback loops
Most signaling systems have negative feedback loops that can perform different functions such as output limiter, and adaptation.
Output limiter
Upon receiving an input signal, the cellular response rapidly increases until a threshold is reached. Beyond this threshold, a negative feedback loop...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Feedback Regulation of Calcium Concentration01:27

Feedback Regulation of Calcium Concentration

Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...