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Related Concept Videos

The Ras Gene02:38

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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.
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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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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
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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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Abnormal Proliferation02:23

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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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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Related Experiment Video

Updated: Oct 4, 2025

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells
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CRAF dimerization with ARAF regulates KRAS-driven tumor growth.

Avinashnarayan Venkatanarayan1, Jason Liang2, Ivana Yen1

  • 1Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Cell Reports
|February 9, 2022
PubMed
Summary
This summary is machine-generated.

Mutant KRAS activates signaling pathways crucial for cancer growth. This study reveals that CRAF protein dimerization, not its kinase activity, is essential for KRAS-mutant lung tumor growth, suggesting new therapeutic strategies.

Keywords:
ARAFBRAFCRAFERKKRASMAPKMEKcancerdimerizationkinase

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Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • KRAS mutations are prevalent in ~30% of human cancers, driving tumor growth via the RAF-MEK-ERK pathway.
  • The specific role of CRAF kinase activity in KRAS-mutant lung tumor progression remains unclear.

Purpose of the Study:

  • To investigate the requirement of CRAF kinase activity versus dimerization in KRAS-mutant lung tumor growth.
  • To elucidate the downstream mechanisms by which CRAF influences tumor progression.

Main Methods:

  • Utilized kinase-dead and dimer-defective CRAF mutants to assess functional requirements.
  • Employed quantitative proteomics to analyze CRAF:ARAF dimerization.
  • Performed gene depletion studies for CRAF and ARAF.
  • Investigated the impact of CRAF depletion on ERK activation and cell-cycle arrest.
  • Tested the efficacy of MEK and ERK inhibitors in rescuing CRAF-loss phenotypes.

Main Results:

  • Subsets of KRAS-mutant tumors demonstrated dependence on CRAF for growth.
  • Kinase-dead CRAF, but not dimer-defective CRAF, rescued growth inhibition, indicating dimerization is critical.
  • Increased CRAF:ARAF dimerization was observed in KRAS-mutant cells.
  • Depletion of both CRAF and ARAF rescued the CRAF-loss phenotype.
  • CRAF depletion led to sustained ERK activation and cell-cycle arrest, which was rescued by MEK/ERK inhibitors.

Conclusions:

  • CRAF dimerization, independent of its kinase activity, is essential for KRAS-mutant lung tumor growth.
  • CRAF regulates MAPK signal intensity downstream of mutant KRAS.
  • Targeting CRAF dimerization or promoting CRAF degradation presents a potential therapeutic strategy for KRAS-mutant cancers.