PMID- 21228924
OWN - NLM
STAT- MEDLINE
DCOM- 20110426
LR  - 20211203
IS  - 1936-2625 (Electronic)
IS  - 1936-2625 (Linking)
VI  - 4
IP  - 1
DP  - 2010 Nov 20
TI  - Morphoproteomic analysis reveals an overexpressed and constitutively activated 
      phospholipase D1-mTORC2 pathway in endometrial carcinoma.
PG  - 13-21
AB  - The mammalian target of rapamycin (MTOR) assembles into two distinct complexes: 
      mTOR complex 1 (mTORC1) is predominantly cytoplasmic and highly responsive to 
      rapamycin, whereas mTOR complex 2 (mTORC2) is both cytoplasmic and nuclear, and 
      relatively resistant to rapamycin. mTORC1 and mTORC2 phosphorylatively regulate 
      their respective downstream effectors p70S6K/4EBP1, and Akt. The resulting 
      activated mTOR pathways stimulate protein synthesis, cellular proliferation, and 
      cell survival. Moreover, phospholipase D (PLD) and its product, phosphatidic acid 
      (PA) have been implicated as one of the upstream activators of mTOR signaling. In 
      this study, we investigated the activation status as well as the subcellular 
      distribution of mTOR, and its upstream regulators and downstream effectors in 
      endometrial carcinomas (ECa) and non-neoplastic endometrial control tissue. Our 
      data show that the mTORC2 activity is selectively elevated in endometrial cancers 
      as evidenced by a predominant nuclear localization of the activated form of mTOR 
      (p-mTOR at Ser2448) in malignant epithelium, accompanied by overexpression of 
      nuclear p-Akt (Ser473), as well as overexpression of vascular endothelial growth 
      factor (VEGF)-A isoform, the latter a resultant of target gene activation by 
      mTORC2 signaling via hypoxia-inducible factor (HIF)-2alpha. In addition, 
      expression of PLD1, one of the two major isoforms of PLD in human, is increased 
      in tumor epithelium. In summary, we demonstrate that the PLD1/PA-mTORC2 signal 
      pathway is overactivated in endometrial carcinomas. This suggests that the 
      rapamycin-insensitive mTORC2 pathway plays a major role in endometrial 
      tumorigenesis and that therapies designed to target the phospholipase D pathway 
      and components of the mTORC2 pathway should be efficacious against ECa.
FAU - Shen, Qi
AU  - Shen Q
AD  - Department of Pathology and Laboratory Medicine, The University of Texas Medical 
      School at Houston, TX 77030, USA.
FAU - Stanton, Melissa L
AU  - Stanton ML
FAU - Feng, Wei
AU  - Feng W
FAU - Rodriguez, Michelle E
AU  - Rodriguez ME
FAU - Ramondetta, Lois
AU  - Ramondetta L
FAU - Chen, Lei
AU  - Chen L
FAU - Brown, Robert E
AU  - Brown RE
FAU - Duan, Xiuzhen
AU  - Duan X
LA  - eng
PT  - Journal Article
DEP - 20101120
PL  - United States
TA  - Int J Clin Exp Pathol
JT  - International journal of clinical and experimental pathology
JID - 101480565
RN  - 0 (Biomarkers, Tumor)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.4 (Phospholipase D)
RN  - EC 3.1.4.4 (phospholipase D1)
SB  - IM
MH  - Biomarkers, Tumor/metabolism
MH  - Carcinoma, Endometrioid/*metabolism/pathology
MH  - Cell Nucleus/metabolism
MH  - Endometrial Neoplasms/*metabolism/pathology
MH  - Endometrium/*metabolism
MH  - Female
MH  - Humans
MH  - Phospholipase D/*metabolism
MH  - Proteomics
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3016100
OTO - NOTNLM
OT  - endometrial carcinoma
OT  - mTORC2
OT  - morphoproteomics
OT  - phospholipase D1
EDAT- 2011/01/14 06:00
MHDA- 2011/04/27 06:00
PMCR- 2010/11/20
CRDT- 2011/01/14 06:00
PHST- 2010/10/20 00:00 [received]
PHST- 2010/11/09 00:00 [accepted]
PHST- 2011/01/14 06:00 [entrez]
PHST- 2011/01/14 06:00 [pubmed]
PHST- 2011/04/27 06:00 [medline]
PHST- 2010/11/20 00:00 [pmc-release]
PST - epublish
SO  - Int J Clin Exp Pathol. 2010 Nov 20;4(1):13-21.