RESUMEN
Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to transformation. Here, we show that ST not only displaces common PP2A B subunits but also promotes A-C subunit interactions with alternative B subunits (B''', striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that STRN4, a member of STRIPAK, is associated with ST and is required for ST-PP2A-induced cell transformation. ST recruitment of STRIPAK facilitates PP2A-mediated dephosphorylation of MAP4K4 and induces cell transformation through the activation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex regulates PP2A specificity and activity.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Fosfoproteínas Fosfatasas/genética , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. We applied the methodology to the RAS pathway and identified nine distinct components that reflect transcriptional activities downstream of RAS and defined several functional states associated with patterns of transcriptional component activation that associates with genomic hallmarks and response to genetic and pharmacological perturbations. These results show that the Onco-GPS is an effective approach to explore the complex landscape of oncogenic cellular states across cancers, and an analytic framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms.