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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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TGF - β Signaling Pathway01:16

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The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
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Activation and Inactivation of G Proteins01:22

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Activation of Integrins01:15

Activation of Integrins

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Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
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Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

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Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
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T Cell Types and Functions01:24

T Cell Types and Functions

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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-&#946; Signaling
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La estructura latente del TGF-β y su activación.

Minlong Shi1, Jianghai Zhu, Rui Wang

  • 1Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Nature
|June 17, 2011
PubMed
Resumen

La activación del factor de crecimiento transformador-beta (TGF-β) implica la unión a la integrina y la fuerza. El análisis estructural revela cómo el prodominio protege el TGF-β, requiriendo fuerza mecánica para liberar el factor de crecimiento.

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Área de la Ciencia:

  • La bioquímica es la bioquímica.
  • Biología Estructural Biología estructural.
  • Biología celular Biología celular.

Sus antecedentes:

  • La transformación del factor de crecimiento beta (TGF-β) es crucial para el crecimiento celular y la homeostasis.
  • El TGF-β se almacena en la matriz extracelular como un complejo latente con su prodominio.
  • La activación requiere unión integrina y fuerza mecánica.

Objetivo del estudio:

  • Para dilucidar las bases estructurales de la formación y activación del complejo TGF-β latente.
  • Comprender el papel de la prodomaína en la regulación de la disponibilidad de TGF-β.

Principales métodos:

  • Cristalografía de rayos X del cerdo dimérico proTGF-β1.1.
  • Análisis de la estructura y las interacciones de las proteínas.

Principales resultados:

  • Reveló un nuevo pliegue de prodominio en forma de anillo que protege el factor de crecimiento.
  • Se ha demostrado que la unión a la integrina por sí sola es insuficiente para la liberación de TGF-β.
  • Identificó un mecanismo dependiente de la fuerza que implica el desabrochamiento de una "jaqueta de fuerza" de prodominio.

Conclusiones:

  • La estructura del prodominio es clave para regular la actividad del TGF-β.
  • La activación dependiente de la fuerza es esencial para liberar el TGF-β activo.
  • Los conocimientos sobre la regulación del TGF-β tienen implicaciones para el desarrollo y la enfermedad.