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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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Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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Small GTPases - Ras and Rho01:24

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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 JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

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Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
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MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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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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Related Experiment Video

Updated: Jan 13, 2026

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

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Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex

Daniel A Bonsor1, Lorenzo I Finci1, Jacob R Potter1

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Nature Communications
|January 10, 2026
PubMed
Summary
This summary is machine-generated.

This study reveals how canonical RAS proteins form weaker complexes with SHOC2-PP1C, impacting cancer. Targeting both canonical RAS (SKP) and MRAS (SMP) complexes offers a strategy to overcome drug resistance in RAS-driven cancers.

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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • RAF activation, crucial for MAPK signaling, involves the SHOC2-RAS-PP1C complex.
  • Canonical RAS isoforms (KRAS, HRAS, NRAS) form lower-affinity complexes than MRAS, yet drive SHOC2-dependent cancers.

Purpose of the Study:

  • To elucidate the structural basis of lower-affinity SHOC2-canonical RAS-PP1C complex formation.
  • To investigate the potential of dual targeting of SHOC2-RAS-PP1C complexes for cancer therapy.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of the SHOC2-KRAS-PP1C complex.
  • Biochemical assays to assess the impact of RAS inhibitors on complex formation.
  • Characterization of a MRAS mutant for dual targeting strategies.

Main Results:

  • The SHOC2-KRAS-PP1C (SKP) complex architecture differs from the SHOC2-MRAS-PP1C (SMP) complex, with fewer contacts and less buried surface area.
  • RAS inhibitors MRTX1133 and RMC-6236 effectively block SKP assembly by altering RAS Switch-I/II conformations.
  • These inhibitors do not affect SMP formation as they do not bind MRAS, but a MRAS mutant susceptible to MRTX1133 demonstrates feasibility of dual targeting.

Conclusions:

  • Isoform-specific differences in SHOC2-RAS-PP1C complex formation are defined.
  • Dual targeting of both SKP and SMP assemblies presents a promising strategy to overcome resistance in RAS-driven cancers.