Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets

The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSCs) are present in tumor cell lines, mouse lung tumors and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GFs) in non-transformed cells with delayed kinetics (4-6 hr), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the pro-senescence transcription factor C/EBPβ in primary MEFs undergoing senescence. Conversely, in tumor cells C/EBPβ activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPβ.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2kMxthO