Video Experimental Relacionado
Updated: Jun 21, 2026
08:45
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
La selectividad de la señalización de la tirosina quinasa del receptor está controlada por un sitio secundario de
Jae Hyun Bae1, Erin Denise Lew, Satoru Yuzawa
1Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Cell
|August 12, 2009
Resumen
Las interacciones del dominio SH2 son clave en la señalización de la tirosina quinasa del receptor. Una nueva investigación revela que los sitios de unión secundaria regulan la selectividad de la fosfolipasa Cgamma, ofreciendo una visión más compleja de las vías de señalización celular.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La señalización celular de las células.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Los dominios SH2 median la señalización transmembrana por las receptoras tirosina quinasas (RTKs) a través del reconocimiento de la fosfotirosina (pY).
- La afinidad de unión de los dominios SH2 a los péptidos que contienen pY es modesta, lo que sugiere un mecanismo demasiado simplificado para la selectividad de las vías de señalización en las células.
Objetivo del estudio:
- Aclarar las bases estructurales y mecánicas de la selectividad de la fosfolipasa Cgamma (PLCγ) en la señalización de FGFR1.
- Para investigar el papel de las interacciones de unión secundaria en la regulación de la selectividad del dominio SH2 in vivo.
Principales métodos:
- Determinación de la estructura cristalina del dominio de la quinasa FGFR1 activado complejo con un fragmento de PLCγ.
- Análisis bioquímicos para evaluar afinidades de unión y eventos de señalización.
- Experimentos que utilizan células cultivadas para validar los hallazgos en un contexto biológico.
Principales resultados:
- La estructura cristalina revela un complejo entre el FGFR1 activado y un fragmento de PLCγ.
- La unión de la fosfolipasa Cgamma (PLCγ) y la selectividad de señalización a través de FGFR1 activado se rigen por las interacciones entre un sitio de unión de dominio SH2 secundario y el dominio de la quinasa FGFR1.
- Estas interacciones ocurren de una manera independiente de la fosforilación.
Conclusiones:
- La selectividad del dominio SH2 está regulada por interacciones independientes de la fosforilación con sitios de unión secundarios.
- Este mecanismo proporciona una comprensión más matizada de cómo la selectividad del dominio SH2 se controla in vivo para mediar procesos celulares específicos.
- Los hallazgos desafían la visión simplificada de la función del dominio SH2 en la señalización de RTK.
Videos de Conceptos Relacionados
01:26Receptor Tyrosine Kinases
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...
01:30Assembly of Signaling Complexes
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,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:22Amplifying Signals via Enzymatic Cascade
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 the...
01:20The JAK-STAT Signaling Pathway
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...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
01:00Enzyme-linked Receptors
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...