Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets.
Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets.
复制标题
DOI：
10.1158/0008-5472.can-17-2353
复制
发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Johnson PF
中科院分区：
文献类型：
--
作者：
Basu SK;Lee S;Salotti J;Basu S;Sakchaisri K;Xiao Z;Walia V;Westlake CJ;Morrison DK;Johnson PF
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.
