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Related Concept Videos

The Ras Gene02:38

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...
Small GTPases - Ras and Rho01:24

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:
Rab Proteins01:14

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
GTPases and their Regulation02:14

GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
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...
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...

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Related Experiment Video

Updated: May 16, 2026

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.

Rachael Baker1, Steven M Lewis, Atsuo T Sasaki

  • 1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Nature Structural & Molecular Biology
|November 27, 2012
PubMed
Summary

Monoubiquitination activates Ras proteins, crucial for cell growth, by blocking their inactivation. This discovery reveals a new pathway for persistent Ras signaling, independent of mutations, potentially driving cancer.

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Area of Science:

  • Molecular biology
  • Cell signaling
  • Biochemistry

Background:

  • Ras GTPases are key regulators of cell growth and differentiation, often dysregulated in cancer.
  • Oncogenic mutations lead to persistent Ras signaling, promoting tumor development.
  • Emerging evidence suggests Ras monoubiquitination is a mechanism for Ras activation.

Purpose of the Study:

  • To elucidate the functional mechanism of human Ras activation by monoubiquitination.
  • To investigate how monoubiquitination affects Ras interaction with regulatory proteins.
  • To understand the implications of Ras monoubiquitination in signaling and disease.

Main Methods:

  • Chemical ubiquitination of purified human Ras protein.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to analyze structural changes.
  • Computational modeling to predict protein interactions.
  • Biochemical assays to measure GTP binding, hydrolysis, and effector/inhibitor interactions.

Main Results:

  • Monoubiquitination minimally impacts Ras binding to guanine nucleotides, GTP hydrolysis, and exchange factor activation.
  • Monoubiquitination significantly impairs Ras interaction with GTPase-activating proteins (GAPs) in a site-specific manner.
  • This impairment leads to sustained Ras activity, mimicking oncogenic signaling.

Conclusions:

  • Ras monoubiquitination represents a novel mechanism for activating Ras signaling.
  • This activation pathway can persist independently of receptor stimulation or oncogenic mutations.
  • Understanding this mechanism offers new insights into cancer development and potential therapeutic targets.