PMID- 23027127
OWN - NLM
STAT- MEDLINE
DCOM- 20131104
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 32
IP  - 35
DP  - 2013 Aug 29
TI  - LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and 
      proliferation via the phosphorylation of Yap.
PG  - 4100-9
LID - 10.1038/onc.2012.431 [doi]
AB  - The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its 
      regulation of cellular metabolism and apical-basal polarity. The best understood 
      mechanism whereby LKB1 limits cell growth is through activation of the 
      AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to 
      control metabolism. As LKB1 is also required for polarized epithelial cells to 
      resist hyperplasia, it is anticipated to function through additional mechanisms. 
      Recently, Yes-associated protein (Yap) has emerged as a transcriptional 
      co-activator that modulates tissue homeostasis in response to cell-cell contact. 
      Thus this study examined a possible connection between Yap and LKB1. Restoration 
      of LKB1 expression in HeLa cells, which lack this tumor suppressor, or 
      short-hairpin RNA knockdown of LKB1 in NTERT immortalized keratinocytes, 
      demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion and 
      proteasomal degradation. The ability of phosphorylation-defective Yap mutants to 
      rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest 
      that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, 
      failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested 
      that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 
      inhibited Yap independently of either AMPK or mTOR activation. These findings 
      reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the 
      inhibition of Yap.
FAU - Nguyen, H B
AU  - Nguyen HB
AD  - Department of Biochemistry and Molecular Biology, Indiana University School of 
      Medicine, Indianapolis, IN 46202, USA.
FAU - Babcock, J T
AU  - Babcock JT
FAU - Wells, C D
AU  - Wells CD
FAU - Quilliam, L A
AU  - Quilliam LA
LA  - eng
GR  - R01 CA151765/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20121001
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - EC 2.7.1.- (LATS1 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.11 (LATS2 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Adenylate Kinase/*physiology
MH  - *Cell Proliferation
MH  - Cell Size
MH  - HeLa Cells
MH  - Humans
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Proteasome Endopeptidase Complex/physiology
MH  - Protein Serine-Threonine Kinases/*physiology
MH  - Stress Fibers/physiology
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - Transcription Factors
MH  - Transcription, Genetic
MH  - Tumor Suppressor Proteins/*physiology
MH  - YAP-Signaling Proteins
PMC - PMC3977597
MID - NIHMS572973
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2012/10/03 06:00
MHDA- 2013/11/05 06:00
PMCR- 2014/04/07
CRDT- 2012/10/03 06:00
PHST- 2012/01/11 00:00 [received]
PHST- 2012/07/02 00:00 [revised]
PHST- 2012/08/07 00:00 [accepted]
PHST- 2012/10/03 06:00 [entrez]
PHST- 2012/10/03 06:00 [pubmed]
PHST- 2013/11/05 06:00 [medline]
PHST- 2014/04/07 00:00 [pmc-release]
AID - onc2012431 [pii]
AID - 10.1038/onc.2012.431 [doi]
PST - ppublish
SO  - Oncogene. 2013 Aug 29;32(35):4100-9. doi: 10.1038/onc.2012.431. Epub 2012 Oct 1.