PMID- 28103956
OWN - NLM
STAT- MEDLINE
DCOM- 20170612
LR  - 20211204
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 15
IP  - 1
DP  - 2017 Jan 19
TI  - Unraveling the regulation of mTORC2 using logical modeling.
PG  - 6
LID - 10.1186/s12964-016-0159-5 [doi]
LID - 6
AB  - BACKGROUND: The mammalian target of rapamycin (mTOR) is a regulator of cell 
      proliferation, cell growth and apoptosis working through two distinct complexes: 
      mTORC1 and mTORC2. Although much is known about the activation and inactivation 
      of mTORC1, the processes controlling mTORC2 remain poorly characterized. 
      Experimental and modeling studies have attempted to explain the regulation of 
      mTORC2 but have yielded several conflicting hypotheses. More specifically, the 
      Phosphoinositide 3-kinase (PI3K) pathway was shown to be involved in this 
      process, but the identity of the kinase interacting with and regulating mTORC2 
      remains to be determined (Cybulski and Hall, Trends Biochem Sci 34:620-7, 2009). 
      METHOD: We performed a literature search and identified 5 published hypotheses 
      describing mTORC2 regulation. Based on these hypotheses, we built logical models, 
      not only for each single hypothesis but also for all combinations and possible 
      mechanisms among them. Based on data provided by the original studies, a 
      systematic analysis of all models was performed. RESULTS: We were able to find 
      models that account for experimental observations from every original study, but 
      do not require all 5 hypotheses to be implemented. Surprisingly, all hypotheses 
      were in agreement with all tested data gathered from the different studies and 
      PI3K was identified as an essential regulator of mTORC2. CONCLUSION: The results 
      and additional data suggest that more than one regulator is necessary to explain 
      the behavior of mTORC2. Finally, this study proposes a new experiment to validate 
      mTORC1 as second essential regulator.
FAU - Thobe, Kirsten
AU  - Thobe K
AUID- ORCID: 0000-0001-8883-0620
AD  - Group for Discrete Biomathematics, Department for Mathematics and Computer 
      Science, Freie Universitaet Berlin, Arnimallee 7, Berlin, 14195, Germany. 
      kirsten.thobe@fu-berlin.de.
AD  - International Research School for Scientific Computing and Computational Biology, 
      Max-Plank Institute for Molecular Genetics, Berlin, Germany. 
      kirsten.thobe@fu-berlin.de.
FAU - Sers, Christine
AU  - Sers C
AD  - Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charite 
      Universitatsmedizin Berlin, Berlin, Germany.
FAU - Siebert, Heike
AU  - Siebert H
AD  - Group for Discrete Biomathematics, Department for Mathematics and Computer 
      Science, Freie Universitaet Berlin, Arnimallee 7, Berlin, 14195, Germany.
AD  - International Research School for Scientific Computing and Computational Biology, 
      Max-Plank Institute for Molecular Genetics, Berlin, Germany.
LA  - eng
PT  - Journal Article
DEP - 20170119
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - *Models, Biological
MH  - Multiprotein Complexes/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC5244562
OTO - NOTNLM
OT  - Cancer signaling
OT  - Logical modeling
OT  - mTORC2 regulation
EDAT- 2017/01/21 06:00
MHDA- 2017/06/13 06:00
PMCR- 2017/01/19
CRDT- 2017/01/21 06:00
PHST- 2016/10/04 00:00 [received]
PHST- 2016/12/20 00:00 [accepted]
PHST- 2017/01/21 06:00 [entrez]
PHST- 2017/01/21 06:00 [pubmed]
PHST- 2017/06/13 06:00 [medline]
PHST- 2017/01/19 00:00 [pmc-release]
AID - 10.1186/s12964-016-0159-5 [pii]
AID - 159 [pii]
AID - 10.1186/s12964-016-0159-5 [doi]
PST - epublish
SO  - Cell Commun Signal. 2017 Jan 19;15(1):6. doi: 10.1186/s12964-016-0159-5.