PMID- 25372051
OWN - NLM
STAT- MEDLINE
DCOM- 20150720
LR  - 20211203
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 7
IP  - 350
DP  - 2014 Nov 4
TI  - PIP4kgamma is a substrate for mTORC1 that maintains basal mTORC1 signaling during 
      starvation.
PG  - ra104
LID - 10.1126/scisignal.2005191 [doi]
AB  - Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases 
      that specifically use phosphatidylinositol 5-monophosphate (PI-5-P) as a 
      substrate to synthesize phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. 
      Suppression of PIP4k function in Drosophila results in smaller cells and reduced 
      target of rapamycin complex 1 (TORC1) signaling. We showed that the gamma isoform of 
      PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kgamma 
      reduced cell mass in cells in which mTORC1 is constitutively activated by Tsc2 
      deficiency. In Tsc2 null cells, mTORC1 activation was partially independent of 
      amino acids or glucose and glutamine. PIP4kgamma knockdown inhibited the 
      nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced 
      basal mTORC1 signaling in wild-type cells. PIP4kgamma was phosphorylated by mTORC1 
      and associated with the complex. Phosphorylated PIP4kgamma was enriched in light 
      microsomal vesicles, whereas the unphosphorylated form was enriched in heavy 
      microsomal vesicles associated with the Golgi. Furthermore, basal mTORC1 
      signaling was enhanced by overexpression of unphosphorylated wild-type PIP4kgamma or 
      a phosphorylation-defective mutant and decreased by overexpression of a 
      phosphorylation-mimetic mutant. Together, these results demonstrate that PIP4kgamma 
      and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly 
      regulated mTORC1 activation during starvation.
CI  - Copyright (c) 2014, American Association for the Advancement of Science.
FAU - Mackey, Ashley M
AU  - Mackey AM
AD  - Boston Biomedical Research Institute, Watertown, MA 02472, USA. Department of 
      Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
FAU - Sarkes, Deborah A
AU  - Sarkes DA
AD  - Boston Biomedical Research Institute, Watertown, MA 02472, USA.
FAU - Bettencourt, Ian
AU  - Bettencourt I
AD  - Boston Biomedical Research Institute, Watertown, MA 02472, USA.
FAU - Asara, John M
AU  - Asara JM
AD  - Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 
      02115, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, 
      USA.
FAU - Rameh, Lucia E
AU  - Rameh LE
AD  - Boston Biomedical Research Institute, Watertown, MA 02472, USA. Department of 
      Medicine, Boston University School of Medicine, Boston, MA 02118, USA. 
      rameh@bu.edu.
LA  - eng
GR  - R01-DK63219-06/DK/NIDDK NIH HHS/United States
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - 5P01CA120964-04/CA/NCI NIH HHS/United States
GR  - 5P30CA006516-46/CA/NCI NIH HHS/United States
GR  - R01 DK063219/DK/NIDDK NIH HHS/United States
GR  - P30 CA006516/CA/NCI NIH HHS/United States
GR  - DK63219-06S1A1/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, American Recovery and Reinvestment Act
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141104
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Multiprotein Complexes)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.- (PIP4kgamma protein, human)
RN  - EC 2.7.1.- (PIP4kgamma protein, mouse)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.68 (1-phosphatidylinositol-4-phosphate 5-kinase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cytoplasm/metabolism
MH  - Fibroblasts/metabolism
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes/*metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
PMC - PMC4579097
MID - NIHMS721801
EDAT- 2014/11/06 06:00
MHDA- 2015/07/21 06:00
PMCR- 2015/09/22
CRDT- 2014/11/06 06:00
PHST- 2014/11/06 06:00 [entrez]
PHST- 2014/11/06 06:00 [pubmed]
PHST- 2015/07/21 06:00 [medline]
PHST- 2015/09/22 00:00 [pmc-release]
AID - 7/350/ra104 [pii]
AID - 10.1126/scisignal.2005191 [doi]
PST - epublish
SO  - Sci Signal. 2014 Nov 4;7(350):ra104. doi: 10.1126/scisignal.2005191.