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相关概念视频

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

Updated: Sep 6, 2025

Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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RAS信号的SHOC2调制的结构基础

Nicholas P D Liau1, Matthew C Johnson1, Saeed Izadi2

  • 1Department of Structural Biology, Genentech, South San Francisco, CA, USA.

Nature
|June 29, 2022
PubMed
概括

在癌症中至关重要的RAS-RAF通路通过SHOC2-PP1C-RAS复杂结构更好地理解. 这揭示了SHOC2如何利用RAS和PP1C激活RAF, 提供新的治疗点.

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科学领域:

  • 分子生物学
  • 结构生物学
  • 癌症研究

背景情况:

  • 在人类癌症中,RAS-RAF通路经常失调.
  • 没有完全理解RAF激酶二分化和激活的机制.
  • 14-3-3蛋白稳定RAF结构,但在二元化之前需要PP1C去化.

研究的目的:

  • 为了阐明SHOC2-PP1C-RAS复合物的结构.
  • 了解SHOC2作为RAF激活中的支架蛋白的作用.
  • 确定RAS异型和SHOC2如何影响RAF的PP1C特异性.

主要方法:

  • 使用冷电子显微镜 (cryo-EM) 来确定SHOC2-PP1C-MRAS复合物的结构.
  • 对复合形成的GTP依赖性和RAS异型偏好的分析.
  • 研究疾病相关突变对复杂组件的影响.

主要成果:

  • 在3 Å分辨率下揭示了SHOC2-PP1C-MRAS复合体的三部分分子结构.
  • SHOC2作为一个支架,把PP1C和MRAS结合在一起.
  • 该研究证明了RAS异型的GTP依赖性,并确定SHOC2和RAS是RAFNTpS的PP1C特异性的驱动因素.

结论:

  • 该结构提供了RAF激活的分子机制的见解.
  • 疾病相关突变可能会破坏复杂的组合.
  • 这些发现表明需要两个RAS分子来激活RAF,并为向抑制剂的开发打开通道.