RESUMEN
We previously reported that the scaffold protein c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) functions in cerebellar granule cell precursors (GCPs) to promote their cell-cycle exit and differentiation. In this study, we used immunocytochemistry to examine the subcellular distribution of JSAP1 in proliferating cultured GCPs. We found that when stimulated with fibroblast growth factor-2 (FGF-2), a factor that promotes GCP differentiation through JNK and extracellular signal-regulated kinase (ERK) signaling, JSAP1 translocated to the plasma membrane and colocalized with activated JNK and ERK. In transfected cells expressing a constitutively activated FGF receptor (FGFR), JSAP1 and the activated FGFR colocalized at the plasma membrane with not only activated but also unphosphorylated and inactive JNK and ERK. These colocalizations did not occur when a mutant JSAP1 lacking the JNK-binding domain was substituted for wild-type JSAP1. Biochemical analyses of transfected cells showed that activated FGFR increased JSAP1's affinity for JNK and ERK and that JSAP1 enhanced FGFR-induced JNK and ERK activation. Collectively, these results suggest that when stimulated by FGFR, JSAP1 translocates to the plasma membrane, where it recruits JNK and ERK and facilitates their activation, leading to the differentiation of cerebellar GCPs.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Diferenciación Celular/fisiología , Membrana Celular/metabolismo , Cerebelo/citología , Proteínas del Tejido Nervioso/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Movimiento Celular , Proliferación Celular , Células Cultivadas , Cerebelo/metabolismo , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Células HEK293 , Humanos , Inmunohistoquímica , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/genética , Unión Proteica/genética , Células Madre/citología , TransfecciónRESUMEN
Different SARS-CoV-2 vaccines are approved in various countries, but few direct comparisons of the antibody responses they stimulate have been reported. We collected plasma specimens in July 2021 from 196 Mongolian participants fully vaccinated with one of four COVID-19 vaccines: Pfizer/BioNTech, AstraZeneca, Sputnik V, and Sinopharm. Functional antibody testing with a panel of nine SARS-CoV-2 viral variant receptor binding domain (RBD) proteins revealed marked differences in vaccine responses, with low antibody levels and RBD-ACE2 blocking activity stimulated by the Sinopharm and Sputnik V vaccines in comparison to the AstraZeneca or Pfizer/BioNTech vaccines. The Alpha variant caused 97% of infections in Mongolia in June and early July 2021. Individuals who recover from SARS-CoV-2 infection after vaccination achieve high antibody titers in most cases. These data suggest that public health interventions such as vaccine boosting, potentially with more potent vaccine types, may be needed to control COVID-19 in Mongolia and worldwide.