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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 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

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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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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Video Experimental Relacionado

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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Bases estructurales para la modulación SHOC2 de la señalización RAS

Nicholas P D Liau1, Matthew C Johnson1, Saeed Izadi2

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

Nature
|June 29, 2022
PubMed
Resumen

La vía RAS-RAF, crucial en el cáncer, se entiende mejor a través de la estructura del complejo SHOC2-PP1C-RAS. Esto revela cómo SHOC2 armazona RAS y PP1C para activar RAF, ofreciendo nuevos objetivos terapéuticos.

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Área de la Ciencia:

  • Biología molecular
  • Biología estructural
  • Investigación sobre el cáncer

Sus antecedentes:

  • La vía RAS-RAF es frecuentemente desregulada en los cánceres humanos.
  • Los mecanismos de la dimerización y activación de la quinasa RAF no se comprenden completamente.
  • La proteína 14-3-3 estabiliza las conformaciones RAF, pero se necesita PP1C para la desfosforilación antes de la dimerización.

Objetivo del estudio:

  • Para aclarar la estructura del complejo SHOC2-PP1C-RAS.
  • Comprender el papel de SHOC2 como una proteína de andamiaje en la activación de RAF.
  • Identificar cómo las isoformas RAS y SHOC2 influyen en la especificidad de PP1C para RAF.

Principales métodos:

  • Se utilizó la crio-microscopía electrónica (cryo-EM) para determinar la estructura del complejo SHOC2-PP1C-MRAS.
  • Análisis de la dependencia de GTP y la preferencia de la isoforma RAS para la formación de complejos.
  • Investigación del impacto de las mutaciones relacionadas con la enfermedad en el ensamblaje complejo.

Principales resultados:

  • Se reveló una arquitectura molecular tripartita del complejo SHOC2-PP1C-MRAS a una resolución de 3 Å.
  • SHOC2 actúa como un andamio, uniendo PP1C y MRAS.
  • El estudio demostró la dependencia de GTP de las isoformas de RAS e identificó SHOC2 y RAS como factores de la especificidad de PP1C para el NTpS RAF.

Conclusiones:

  • La estructura proporciona información sobre los mecanismos moleculares de la activación de la RAF.
  • Las mutaciones asociadas a enfermedades pueden interrumpir el ensamblaje complejo.
  • Los hallazgos sugieren la necesidad de dos moléculas RAS para la activación de la RAF y abren vías para el desarrollo de inhibidores dirigidos.