Video Experimental Relacionado
Updated: Sep 10, 2025
08:45
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
6.3K
Las variantes genéticas SHP2 en las RASopatías asociadas a NSML interrumpen el eje de señalización del factor de
Sravan Perla1, Amy L Stiegler1, Jae-Sung Yi1
1Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
Resumen
El síndrome de Noonan con lentigines múltiples (NSML) interrumpe el crecimiento cardíaco al afectar el reclutamiento de SHP2 a la PZR, lo que lleva a niveles alterados de IRX y BMP10. La orientación hacia esta vía puede tratar la cardiomiopatía hipertrófica asociada a la RASopatía (CMH).
Área de la Ciencia:
- Biología cardiovascular
- La genética
- La medicina molecular
Sus antecedentes:
- El síndrome de Noonan con lentigines múltiples (NSML) es un trastorno genético relacionado con mutaciones de PTPN11.
- La mayoría de los pacientes con NSML desarrollan cardiomiopatía hipertrófica (HCM), un desafío clínico significativo.
- Los mecanismos moleculares que vinculan NSML a HCM requieren una mayor aclaración.
Objetivo del estudio:
- Investigar el papel del reclutamiento de SHP2 en PZR en la hipertrofia cardíaca asociada a NSML.
- Identificar la vía de señalización que involucra a los factores de transcripción IRX y BMP10 en la patogénesis de la NSML.
- Explorar objetivos terapéuticos potenciales para la CMH relacionada con la LMSN.
Principales métodos:
- Se utilizaron modelos de ratón NSML con mutaciones específicas de PZR y tratamiento con dosis bajas de dasatinib.
- Interacciones proteína-proteína analizadas, incluida la unión SHP2-PZR y SHP2-c-Src a través de estudios estructurales.
- Niveles cuantificados de expresión génica y proteica de IRX3, IRX5 y BMP10 en tejidos cardíacos.
Principales resultados:
- El reclutamiento de SHP2 a la PZR fosforilada por tirosilo es crucial para el fenotipo cardíaco de NSML.
- Esta interacción regula los factores de transcripción de la homeobox iroquesa (IRX) (IRX3 e IRX5) que suprimen el BMP10.
- La interacción disfuncional SHP- PZR altera la activación de IRX, lo que lleva a un aumento de BMP10 y hipertrofia cardíaca.
- El tratamiento con dasatinib normalizó los niveles de IRX y BMP10 en ratones con NSML.
Conclusiones:
- Las variantes SHP2 asociadas a NSML interrumpen el eje de señalización PZR-SHP2-IRX-BMP10.
- Este eje es un regulador clave del crecimiento cardíaco posnatal e implicado en NSML-HCM.
- Dirigirse a la interacción PZR-SHP2 o a la señalización posterior ofrece una estrategia terapéutica potencial para la CMH asociada a la RASopatía.
Palabras clave:
Síndrome de Noonan con múltiples lentigenesDominio SH2cardiomiopatía hipertróficaLas fosfatasas de proteína tirosinaFactores de transcripciónMás Videos Relacionados
09:37Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
9.9K
09:34Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
34.0K
Videos de Conceptos Relacionados
02:38The Ras Gene
6.4K
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...
Ras is a...
6.4K
02:23Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
01:24Small GTPases - Ras and Rho
4.2K
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:
Three regulatory proteins control their activity:
4.2K
01:20The JAK-STAT Signaling Pathway
9.2K
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...
9.2K
01:33Pleiotropy
41.1K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
41.1K
01:19Interactions Between Signaling Pathways
6.4K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.4K