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相关概念视频

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

Small GTPases - Ras and Rho

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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.
Three regulatory proteins control their activity:
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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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相关实验视频

Updated: Jan 13, 2026

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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SHOC2-KRAS-PP1C复合体的结构揭示了RAS异型特异性决定因素,以及对RAS抑制剂针对复合体组合的洞察力.

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
概括

这项研究揭示了正规RAS蛋白如何与SHOC2-PP1C形成较弱的复合体,影响癌症. 针对正规RAS (SKP) 和MRAS (SMP) 综合体提供了一种克服RAS驱动癌症耐药性的策略.

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

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相关实验视频

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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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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科学领域:

  • 分子生物学分子生物学
  • 结构生物学 结构生物学
  • 在瘤学瘤学.

背景情况:

  • 对于MAPK信号发送至关重要的RAF激活涉及SHOC2-RAS-PP1C复合体.
  • 规范RAS异型 (KRAS,HRAS,NRAS) 形成的复合体的亲和力低于MRAS,但驱动SHOC2-依赖的癌症.

研究的目的:

  • 为了阐明较低亲和度的SHOC2-规范RAS-PP1C复合体形成的结构基础.
  • 研究SHOC2-RAS-PP1C复合物的双重向在癌症治疗中的潜力.

主要方法:

  • 低温电子显微镜 (cryo-EM) 用于确定SHOC2-KRAS-PP1C复合物的结构.
  • 生物化学测试,以评估RAS抑制剂对复合体形成的影响.
  • 用于双重准策略的MRAS突变体的表征.

主要成果:

  • SHOC2-KRAS-PP1C (SKP) 综合体架构与SHOC2-MRAS-PP1C (SMP) 综合体不同,接触点较少,表面积较少.
  • RAS 抑制剂 MRTX1133 和 RMC-6236 通过改变 RAS 开关 I/II 结构,有效地阻止 SKP 组件.
  • 这些抑制剂不会影响SMP形成,因为它们不会结合MRAS,但对MRTX1133敏感的MRAS突变体表明双重向的可行性.

结论:

  • 定义了SHOC2-RAS-PP1C复合体形成中的异型特异性差异.
  • 对SKP和SMP组件的双重定位是克服RAS驱动癌症抵抗力的有希望的策略.