PMID- 25180228
OWN - NLM
STAT- MEDLINE
DCOM- 20141231
LR  - 20211203
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 33
IP  - 21
DP  - 2014 Nov 3
TI  - Opposing activities of the Ras and Hippo pathways converge on regulation of YAP 
      protein turnover.
PG  - 2447-57
LID - 10.15252/embj.201489385 [doi]
AB  - Cancer genomes accumulate numerous genetic and epigenetic modifications. Yet, 
      human cellular transformation can be accomplished by a few genetically defined 
      elements. These elements activate key pathways required to support replicative 
      immortality and anchorage independent growth, a predictor of tumorigenesis in 
      vivo. Here, we provide evidence that the Hippo tumor suppressor pathway is a key 
      barrier to Ras-mediated cellular transformation. The Hippo pathway targets YAP1 
      for degradation via the betaTrCP-SCF ubiquitin ligase complex. In contrast, the Ras 
      pathway acts oppositely, to promote YAP1 stability through downregulation of the 
      ubiquitin ligase complex substrate recognition factors SOCS5/6. Depletion of 
      SOCS5/6 or upregulation of YAP1 can bypass the requirement for oncogenic Ras in 
      anchorage independent growth in vitro and tumor formation in vivo. Through the 
      YAP1 target, Amphiregulin, Ras activates the endogenous EGFR pathway, which is 
      required for transformation. Thus, the oncogenic activity of Ras(V12) depends on 
      its ability to counteract Hippo pathway activity, creating a positive feedback 
      loop, which depends on stabilization of YAP1.
CI  - (c) 2014 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Hong, Xin
AU  - Hong X
AD  - Institute of Molecular and Cell Biology, Singapore City, Singapore Department of 
      Biological Sciences, National University of Singapore, Singapore City, Singapore.
FAU - Nguyen, Hung Thanh
AU  - Nguyen HT
AD  - Duke-NUS Graduate Medical School, Singapore City, Singapore.
FAU - Chen, Qingfeng
AU  - Chen Q
AD  - Institute of Molecular and Cell Biology, Singapore City, Singapore Singapore-MIT 
      Alliance for Research, and Technology, Singapore City, Singapore.
FAU - Zhang, Rui
AU  - Zhang R
AD  - Department of Genetics, Stanford University, Palo Alto, CA, USA.
FAU - Hagman, Zandra
AU  - Hagman Z
AD  - Department of Cellular and Molecular Medicine, University of Copenhagen, 
      Copenhagen, Denmark.
FAU - Voorhoeve, P Mathijs
AU  - Voorhoeve PM
AD  - Duke-NUS Graduate Medical School, Singapore City, Singapore.
FAU - Cohen, Stephen M
AU  - Cohen SM
AD  - Institute of Molecular and Cell Biology, Singapore City, Singapore Department of 
      Biological Sciences, National University of Singapore, Singapore City, Singapore 
      scohen@imcb.a-star.edu.sg.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140901
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (BTRC protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (SOCS5 protein, human)
RN  - 0 (SOCS6 protein, human)
RN  - 0 (Suppressor of Cytokine Signaling Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - 0 (beta-Transducin Repeat-Containing Proteins)
RN  - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
CIN - EMBO J. 2014 Nov 3;33(21):2437-8. PMID: 25257311
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Cell Transformation, Neoplastic/genetics/*metabolism/pathology
MH  - ErbB Receptors/genetics/metabolism
MH  - HEK293 Cells
MH  - Hippo Signaling Pathway
MH  - Humans
MH  - Phosphoproteins/genetics/*metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Protein Stability
MH  - SKP Cullin F-Box Protein Ligases/genetics/metabolism
MH  - *Signal Transduction
MH  - Suppressor of Cytokine Signaling Proteins/genetics/metabolism
MH  - Transcription Factors
MH  - Up-Regulation/genetics
MH  - YAP-Signaling Proteins
MH  - beta-Transducin Repeat-Containing Proteins/immunology/metabolism
MH  - ras Proteins/genetics/*metabolism
PMC - PMC4283404
OTO - NOTNLM
OT  - Hippo pathway
OT  - RasV12
OT  - anchorage independence
OT  - primary cell transformation
OT  - tumor suppressor
EDAT- 2014/09/03 06:00
MHDA- 2015/01/01 06:00
PMCR- 2015/11/03
CRDT- 2014/09/03 06:00
PHST- 2014/09/03 06:00 [entrez]
PHST- 2014/09/03 06:00 [pubmed]
PHST- 2015/01/01 06:00 [medline]
PHST- 2015/11/03 00:00 [pmc-release]
AID - embj.201489385 [pii]
AID - 10.15252/embj.201489385 [doi]
PST - ppublish
SO  - EMBO J. 2014 Nov 3;33(21):2447-57. doi: 10.15252/embj.201489385. Epub 2014 Sep 1.