PMID- 25378594
OWN - NLM
STAT- MEDLINE
DCOM- 20150311
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 193
IP  - 12
DP  - 2014 Dec 15
TI  - Rictor negatively regulates high-affinity receptors for IgE-induced mast cell 
      degranulation.
PG  - 5924-32
LID - 10.4049/jimmunol.1303495 [doi]
AB  - Rictor is a regulatory component of the mammalian target of rapamycin (mTOR) 
      complex 2 (mTORC2). We have previously demonstrated that rictor expression is 
      substantially downregulated in terminally differentiated mast cells as compared 
      with their immature or transformed counterparts. However, it is not known whether 
      rictor and mTORC2 regulate mast cell activation. In this article, we show that 
      mast cell degranulation induced by aggregation of high-affinity receptors for IgE 
      (FcepsilonRI) is negatively regulated by rictor independently of mTOR. We found that 
      inhibition of mTORC2 by the dual mTORC1/mTORC2 inhibitor Torin1 or by 
      downregulation of mTOR by short hairpin RNA had no impact on FcepsilonRI-induced 
      degranulation, whereas downregulation of rictor itself resulted in an increased 
      sensitivity ( approximately 50-fold) of cells to FcepsilonRI aggregation with enhancement of 
      degranulation. This was linked to a similar enhancement in calcium mobilization 
      and cytoskeletal rearrangement attributable to increased phosphorylation of LAT 
      and PLCgamma1. In contrast, degranulation and calcium responses elicited by the G 
      protein-coupled receptor ligand, C3a, or by thapsigargin, which induces a 
      receptor-independent calcium signal, was unaffected by rictor knockdown. 
      Overexpression of rictor, in contrast with knockdown, suppressed FcepsilonRI-mediated 
      degranulation. Taken together, these data provide evidence that rictor is a 
      multifunctional signaling regulator that can regulate FcepsilonRI-mediated 
      degranulation independently of mTORC2.
FAU - Smrz, Daniel
AU  - Smrz D
AD  - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD 20892; and 
      daniel.smrz@lfmotol.cuni.cz.
FAU - Cruse, Glenn
AU  - Cruse G
AD  - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD 20892; and.
FAU - Beaven, Michael A
AU  - Beaven MA
AD  - Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, 
      National Institutes of Health, Bethesda, MD 20892.
FAU - Kirshenbaum, Arnold
AU  - Kirshenbaum A
AD  - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD 20892; and.
FAU - Metcalfe, Dean D
AU  - Metcalfe DD
AD  - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD 20892; and.
FAU - Gilfillan, Alasdair M
AU  - Gilfillan AM
AD  - Laboratory of Allergic Diseases, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD 20892; and.
LA  - eng
GR  - ZIA AI000965-09/Intramural NIH HHS/United States
GR  - ZIA HL000993-24/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20141105
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Actins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Protein Aggregates)
RN  - 0 (RICTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Receptors, IgE)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Actins/metabolism
MH  - Calcium Signaling
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Degranulation/genetics/*immunology
MH  - Cell Line
MH  - Enzyme Activation
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mast Cells/*immunology/*metabolism
MH  - Protein Aggregates
MH  - Protein Transport
MH  - RNA Interference
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Receptors, IgE/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4258480
MID - NIHMS636597
COIS- Conflict of interests The authors have no financial or commercial conflict of 
      interest.
EDAT- 2014/11/08 06:00
MHDA- 2015/03/12 06:00
PMCR- 2015/12/15
CRDT- 2014/11/08 06:00
PHST- 2014/11/08 06:00 [entrez]
PHST- 2014/11/08 06:00 [pubmed]
PHST- 2015/03/12 06:00 [medline]
PHST- 2015/12/15 00:00 [pmc-release]
AID - jimmunol.1303495 [pii]
AID - 10.4049/jimmunol.1303495 [doi]
PST - ppublish
SO  - J Immunol. 2014 Dec 15;193(12):5924-32. doi: 10.4049/jimmunol.1303495. Epub 2014 
      Nov 5.