PMID- 31451768
OWN - NLM
STAT- MEDLINE
DCOM- 20191126
LR  - 20221114
IS  - 1476-4679 (Electronic)
IS  - 1465-7392 (Linking)
VI  - 21
IP  - 9
DP  - 2019 Sep
TI  - Protein kinase N controls a lysosomal lipid switch to facilitate nutrient 
      signalling via mTORC1.
PG  - 1093-1101
LID - 10.1038/s41556-019-0377-3 [doi]
AB  - Mechanistic target of rapamycin (mTOR) kinase functions in two multiprotein 
      complexes: lysosomal mTOR complex 1 (mTORC1) and mTORC2 at the plasma membrane. 
      mTORC1 modulates the cell response to growth factors and nutrients by increasing 
      protein synthesis and cell growth, and repressing the autophagy-lysosomal 
      pathway(1-4); however, dysfunction in mTORC1 is implicated in various 
      diseases(3,5,6). mTORC1 activity is regulated by phosphoinositide lipids(7-10). 
      Class I phosphatidylinositol-3-kinase (PI3K)-mediated production of 
      phosphatidylinositol-3,4,5-trisphosphate(6,11) at the plasma membrane stimulates 
      mTORC1 signalling, while local synthesis of phosphatidylinositol-3,4-bisphosphate 
      by starvation-induced recruitment of class II PI3K-beta (PI3KC2-beta) to lysosomes 
      represses mTORC1 activity(12). How the localization and activity of PI3KC2-beta are 
      regulated by mitogens is unknown. We demonstrate that protein kinase N (PKN) 
      facilitates mTORC1 signalling by repressing PI3KC2-beta-mediated 
      phosphatidylinositol-3,4-bisphosphate synthesis downstream of mTORC2. Active PKN2 
      phosphorylates PI3KC2-beta to trigger PI3KC2-beta complex formation with inhibitory 
      14-3-3 proteins. Conversely, loss of PKN2 or inactivation of its target 
      phosphorylation site in PI3KC2-beta represses nutrient signalling via mTORC1. These 
      results uncover a mechanism that couples mTORC2-dependent activation of PKN2 to 
      the regulation of mTORC1-mediated nutrient signalling by local lipid signals.
FAU - Wallroth, Alexander
AU  - Wallroth A
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), Berlin, Germany.
FAU - Koch, Philipp A
AU  - Koch PA
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), Berlin, Germany.
FAU - Marat, Andrea L
AU  - Marat AL
AUID- ORCID: 0000-0001-8571-4253
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), Berlin, Germany.
FAU - Krause, Eberhard
AU  - Krause E
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), Berlin, Germany.
FAU - Haucke, Volker
AU  - Haucke V
AUID- ORCID: 0000-0003-3119-6993
AD  - Leibniz-Forschungsinstitut fur Molekulare Pharmakologie (FMP), Berlin, Germany. 
      haucke@fmp-berlin.de.
AD  - Faculty of Biology, Chemistry and Pharmacy, Freie Universitat Berlin, Berlin, 
      Germany. haucke@fmp-berlin.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190826
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Lipids)
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 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Proliferation/physiology
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - *Lipids
MH  - Lysosomes/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Multiprotein Complexes/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2019/08/28 06:00
MHDA- 2019/11/27 06:00
CRDT- 2019/08/28 06:00
PHST- 2019/01/08 00:00 [received]
PHST- 2019/07/19 00:00 [accepted]
PHST- 2019/08/28 06:00 [pubmed]
PHST- 2019/11/27 06:00 [medline]
PHST- 2019/08/28 06:00 [entrez]
AID - 10.1038/s41556-019-0377-3 [pii]
AID - 10.1038/s41556-019-0377-3 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2019 Sep;21(9):1093-1101. doi: 10.1038/s41556-019-0377-3. Epub 
      2019 Aug 26.