PMID- 22619175
OWN - NLM
STAT- MEDLINE
DCOM- 20121009
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 28
DP  - 2012 Jul 6
TI  - Threonine-120 phosphorylation regulated by phosphoinositide-3-kinase/Akt and 
      mammalian target of rapamycin pathway signaling limits the antitumor activity of 
      mammalian sterile 20-like kinase 1.
PG  - 23698-709
LID - 10.1074/jbc.M112.358713 [doi]
AB  - Mst1/Stk4, a hippo-like serine-threonine kinase, is implicated in many cancers, 
      including prostate cancer. However, the mechanisms regulating Mst1 remain 
      obscure. Here, we characterized the effects of phospho-Thr-120 on Mst1 in 
      prostate cancer cells. We demonstrated that phospho-Thr-120 did not alter the 
      nuclear localization or cleavage of Mst1 in a LNCaP or castration-resistant C4-2 
      prostate tumor cell model, as revealed by a mutagenesis approach. Phospho-Thr-120 
      appeared to be specific to cancer cells and predominantly localized in the 
      nucleus. In contrast, phospho-Thr-183, a critical regulator of Mst1 cell death, 
      was exclusively found in the cytoplasm. As assessed by immunohistochemistry, a 
      similar distribution of phospho-Mst1-Thr-120/Thr-183 was also observed in a 
      prostate cancer specimen. In addition, the blockade of PI3K signaling by a small 
      molecule inhibitor, LY294002, increased cytoplasmic phospho-Mst1-Thr-183 without 
      having a significant effect on nuclear phospho-Mst1-Thr-120. However, the 
      attenuation of mammalian target of rapamycin (mTOR) activity by a selective 
      pharmacologic inhibitor, Ku0063794 or CCI-779, caused the up-regulation of 
      nuclear phospho-Mst1-Thr-120 without affecting cytoplasmic phospho-Mst1-Thr-183. 
      This suggests that PI3K and mTOR pathway signaling differentially regulate 
      phospho-Mst1-Thr-120/Thr-183. Moreover, mutagenesis and RNAi data revealed that 
      phospho-Thr-120 resulted in C4-2 cell resistance to mTOR inhibition and reduced 
      the Mst1 suppression of cell growth and androgen receptor-driven gene expression. 
      Collectively, these findings indicate that phospho-Thr-120 leads to the loss of 
      Mst1 functions, supporting cancer cell growth and survival.
FAU - Collak, Filiz Kisaayak
AU  - Collak FK
AD  - Department of Medicine and Biomedical Sciences, Samuel Oschin Comprehensive 
      Cancer Institute, Los Angeles, California 90048, USA.
FAU - Yagiz, Kader
AU  - Yagiz K
FAU - Luthringer, Daniel J
AU  - Luthringer DJ
FAU - Erkaya, Bahriye
AU  - Erkaya B
FAU - Cinar, Bekir
AU  - Cinar B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120522
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Chromones)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 2ZD004190S (Threonine)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 624KN6GM2T (temsirolimus)
RN  - 81HJG228AB (Ku 0063794)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.11 (STK4 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Nucleus/metabolism
MH  - Chromones/pharmacology
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Morpholines/pharmacology
MH  - Neoplasms, Experimental/genetics/metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Prostatic Neoplasms/genetics/metabolism/pathology
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Pyrimidines/pharmacology
MH  - RNA Interference
MH  - Signal Transduction/drug effects
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Threonine/*metabolism
MH  - Transplantation, Heterologous
MH  - Tumor Burden
PMC - PMC3390644
EDAT- 2012/05/24 06:00
MHDA- 2012/10/10 06:00
PMCR- 2013/07/06
CRDT- 2012/05/24 06:00
PHST- 2012/05/24 06:00 [entrez]
PHST- 2012/05/24 06:00 [pubmed]
PHST- 2012/10/10 06:00 [medline]
PHST- 2013/07/06 00:00 [pmc-release]
AID - S0021-9258(20)43377-0 [pii]
AID - M112.358713 [pii]
AID - 10.1074/jbc.M112.358713 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Jul 6;287(28):23698-709. doi: 10.1074/jbc.M112.358713. Epub 
      2012 May 22.