Oncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation

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• 作者：Ruth Nussinov^a ; ^b ; ^{NussinoR@helix.nih.gov" class="auth_mail" title="E-mail the corresponding author} ; Chung-Jung Tsai^a ; Hyunbum Jang^a ; Tamá ; s Korcsmá ; ros^c ; ^d ; Peter Csermely^e
• 关键词：YAP1 ; Yes ; MAPK ; mitogen-activated protein kinase ; ERK ; extracellular signal-regulated kinase ; eIF4E ; eukaryotic translation initiation factor 4E ; PI3K ; phosphatidylinositide-3-kinase ; WNT ; Wingless-type mouse mammary tumor virus integration site family member ; GPCRs ; G protein-coupled receptors ; TNF ; tumor necrosis factor ; mTOR ; mammalian target of rapamycin ; TLR ; Toll-like receptor ; JAK ; Janus kinase ; STAT ; signal transducer and activator of transcription ; CDK ; Cyclin-dependent kinase ; pRb ; re
• 刊名：Seminars in Cell & Developmental Biology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：58
• 期：Complete
• 页码：79-85
• 全文大小：1713 K

文摘

Why are YAP1 and c-Myc often overexpressed (or activated) in KRAS-driven cancers and drug resistance? Here, we propose that there are two independent pathways in tumor proliferation: one includes MAPK/ERK and PI3K/A kt/mTOR; and the other consists of pathways leading to the expression (or activation) of YAP1 and c-Myc. KRAS contributes through the first. MYC is regulated by e.g. β-catenin, Notch and Hedgehog. We propose that YAP1 and ERK accomplish similar roles in cell cycle control, as do β-catenin and PI3K. This point is compelling, since the question of how YAP1 rescues K-Ras or B-Raf ablation has recently captured much attention, as well as the mechanism of resistance to PI3K inhibitors. The similarity in cell cycle actions of β-catenin and PI3K can also clarify the increased aggressiveness of lung cancer when both K-Ras and β-catenin operate. Thus, we propose that the two pathways can substitute one another – or together amplify each other – in promoting proliferation. This new understanding of the independence and correspondence of the two pathways in cancer – MAPK/ERK and PI3K/Akt/mTOR; and YAP1 and c-Myc – provide a coherent and significant picture of signaling-driven oncogenic proliferation and may help in judicious, pathway-based drug discovery.