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The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...

Interactions Between Signaling Pathways

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 Cascade

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...

Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

MAPK Signaling Cascades

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...

The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...

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Related Experiment Video

Updated: Jul 8, 2026

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

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Signal processing at the Ras circuit: what shapes Ras activation patterns?

N I Markevich¹, G Moehren, O V Demin

¹Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Systems Biology

|October 21, 2006

Summary

This study reveals how Ras signaling integrates cellular signals, showing transient RasGAP activation explains sustained Ras-GTP patterns crucial for cell fate and cancer development.

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Area of Science:

Systems biology
Cellular signal transduction
Molecular signaling pathways

Background:

Ras proteins act as critical molecular switches controlling cell fate.
Ras activity is regulated by intrinsic GTPase activity and external signaling factors.
Dysregulation of Ras signaling is implicated in various cancers.

Purpose of the Study:

To quantitatively understand Ras signaling integration using a systems biology approach.
To elucidate the mechanisms underlying sustained Ras-GTP signaling in response to epidermal growth factor (EGF).
To investigate the role of Ras GTPase-activating protein (RasGAP) in regulating Ras activity.

Main Methods:

Systems biology approach integrating experimental data and kinetic modeling.
Analysis of Ras-GTP levels in hepatocytes stimulated with EGF.
Development of a comprehensive kinetic model of the EGF receptor (EGFR) network.

Main Results:

Basal Ras-GTP levels are highly sensitive to GTP-hydrolysis rates, explaining Ras mutant carcinogenicity.
Transient SOS activation and sustained Ras-GTP patterns were observed upon EGF stimulation.
Transient RasGAP activation, not just SOS signal switching, is required to explain observed signaling dynamics.
A kinetic model incorporating EGFR-mediated recruitment and complex formation of RasGAP with p190 RhoGAP explained hepatocyte data.

Conclusions:

Transient RasGAP activation is a key mechanism for sustained Ras-GTP signaling.
The interplay between EGFR, SOS, RasGAP, and p190 RhoGAP regulates cellular signal transduction.
Integrated dynamic analysis combined with experimental monitoring can dissect complex signaling networks.