title: Oncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation.
abstract: 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.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Gut Health and Food Safety Programme, Institute of Food Research, and TGAC, Norwich Research Park, Norwich NR4 7UA, UK; TGAC, The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Tamás
authors.initials: T
authors.lastname: Korcsmáros
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 2, H-1428 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle; D006801:Humans; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051176:beta Catenin; D018631:ras Proteins
keywords: Cancer; Cellular pathways; Drug resistance; Hippo; K-Ras; Myc; Proliferation; WNT