MOB3A Bypasses BRAF and RAS Oncogene-Induced Senescence by Engaging the Hippo Pathway

Oncogenic activation of the RTK-RAS-RAF-MEK-ERK pathway occurs in approximately 25% of all human cancers, yet activated RAS, BRAF, or MEK expression in primary cells leads to a prolonged and predominantly irreversible cell-cycle arrest termed oncogene-induced senescence (OIS). OIS acts as an intrinsic tumor suppressor mechanism, serving as a barrier to tumor progression. Screening a library of activated kinases and kinase-regulatory proteins we identified MOB3A, a Mps-one binder coactivator (MOB) protein family member, whose constitutive expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals. MOB3A is one of seven human MOB genes, which are highly conserved from yeast to human and that function to activate the Hippo pathway kinases (MST/LATS) or NDR kinases through direct association. Here we show that within the MOB family of genes MOB3A and C are unique in their ability to allow primary cell proliferation in the face of sustained oncogene signaling. Unlike the canonical MOB1A/B proteins, MOB3A inhibits Hippo/MST/LATS signaling and constitutive MOB3A membrane localization phenocopies OIS bypass seen with elevated YAP expression. Moreover, inhibition of MOB3 family member expression results in decreased proliferation and tumor growth of cancer cell lines. Together these data identify MOB3A's role in bypass of oncogene induced senescence and its role as a Hippo pathway inhibitor. These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.