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関連する概念動画

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 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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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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The JAK-STAT Signaling Pathway01:20

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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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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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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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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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Updated: Sep 6, 2025

Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis

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RAS信号のSHOC2調節のための構造的基礎

Nicholas P D Liau1, Matthew C Johnson1, Saeed Izadi2

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

Nature
|June 29, 2022
PubMed
まとめ

がんにおいて重要なRAS-RAF経路は,SHOC2-PP1C-RAS複合体の構造によってよりよく理解されています. これは,SHOC2がRASとPP1Cを活性化して,新しい治療目標を提供する方法を示しています.

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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科学分野:

  • 分子生物学
  • 構造生物学
  • 癌の研究

背景:

  • RAS-RAF経路はヒトの癌では頻繁に乱れている.
  • RAFキナーゼの二分化と活性化のメカニズムは完全に理解されていません.
  • 14-3-3タンパク質はRAF構造を安定させるが,PP1Cは二酸化前に脱酸化に必要である.

研究 の 目的:

  • SHOC2-PP1C-RAS複合体の構造を明らかにする.
  • SHOC2がRAFの活性化における構造タンパク質としての役割を理解する.
  • RASアイソフォームとSHOC2がRAFのPP1C特異性をどのように影響するか確認する.

主な方法:

  • SHOC2- PP1C- MRAS複合体の構造を決定するために,冷凍電子顕微鏡 (冷凍EM) が使用されました.
  • 複合体の形成に対するGTP依存とRAS同型偏好の分析
  • 病気に関連する突然変異が複合組織に与える影響の調査

主要な成果:

  • 3 Åの解像度でSHOC2-PP1C-MRAS複合体の三重分子構造が明らかになった.
  • SHOC2はPP1CとMRASを結びつける 支架のような役割を果たします
  • この研究は,RAF NTpSにおけるPP1C特異性の要因として,RASのGTP依存性を示し,SHOC2とRASを特定した.

結論:

  • 構造はRAFの活性化の分子機構の洞察を提供します.
  • 病気に関連した突然変異は 複雑な組み立てを妨げる可能性があります
  • この発見は,RAFの活性化のために2つのRAS分子が必要であり,ターゲットを絞った阻害剤の開発への道を開くことを示唆している.