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Related Concept Videos

The Ras Gene02:38

The Ras Gene

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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...
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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...
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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.
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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Rab Proteins01:14

Rab Proteins

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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.
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Rab Cascades01:25

Rab Cascades

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Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
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Related Experiment Video

Updated: Jun 24, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins.

Wout Magits1, Mikhail Steklov1, Hyunbum Jang2

  • 1VIB-KU Leuven Center for Cancer Biology, VIB, 3000, Leuven, Belgium.

The EMBO Journal
|June 10, 2024
PubMed
Summary
This summary is machine-generated.

Lysine 128 ubiquitination of RAS proteins enhances their interaction with GTPase-activating proteins (GAPs), inhibiting cancer cell growth. Reduced ubiquitination promotes RAS signaling and pancreatic tumor development.

Keywords:
NF1RAS InteractomeRAS SignalingSenescence-Associated Secretory PhenotypeUbiquitination

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Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The RAS signaling pathway is frequently dysregulated in various cancers.
  • Mechanisms controlling RAS activity in human pathologies require further elucidation.
  • Lysine 128 (K128) ubiquitination of NRAS and KRAS is a prevalent modification decreased in cancer.

Purpose of the Study:

  • To investigate the functional role of K128 ubiquitination in RAS signaling and cancer.
  • To determine how K128 ubiquitination impacts RAS interactions with GTPase-activating proteins (GAPs).
  • To explore the consequences of altered K128 ubiquitination in both wild-type and mutant RAS-driven cancers.

Main Methods:

  • Investigated K128 ubiquitination in cancer cell lines and tissues.
  • Utilized cell culture stimulation with growth factors and cytokines.
  • Analyzed RAS-GAP interactions and downstream signaling pathways (RAL/TBK1).
  • Assessed the impact on tumor growth and senescence-associated secretory phenotype.

Main Results:

  • K128 ubiquitination enhances binding to GAPs (NF1, RASA1), promoting GTP hydrolysis and limiting wild-type RAS activation.
  • Transient K128 ubiquitination restricts RAS activation upon growth factor stimulation.
  • In KRAS mutant cells, K128 ubiquitination suppresses tumor growth by inhibiting RAL/TBK1 signaling and autocrine circuits.
  • Reduced K128 ubiquitination activates both wild-type and mutant RAS, inducing a senescence-associated secretory phenotype and promoting pancreatic tumorigenesis.

Conclusions:

  • K128 ubiquitination acts as a crucial negative regulator of RAS signaling.
  • This modification influences RAS activity in both normal and cancerous conditions.
  • Targeting K128 ubiquitination may offer therapeutic strategies for RAS-driven cancers, particularly pancreatic cancer.