PMID- 24790108
OWN - NLM
STAT- MEDLINE
DCOM- 20141024
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 24
DP  - 2014 Jun 13
TI  - Mis-regulation of mammalian target of rapamycin (mTOR) complexes induced by 
      albuminuria in proximal tubules.
PG  - 16790-801
LID - 10.1074/jbc.M114.549717 [doi]
AB  - High albumin concentrations in the proximal tubule of the kidney causes 
      tubulointerstitial injury, but how this process occurs is not completely known. 
      To address the signal transduction pathways mis-regulated in renal injury, we 
      studied the modulation of mammalian target of rapamycin (mTOR) complexes by 
      physiologic and pathophysiologic albumin concentrations in proximal tubule cells. 
      Physiologic albumin concentrations activated the PI3K/mTORC2/PKB/mTORC1/S6 kinase 
      (S6K) pathway, but pathophysiologically high albumin concentrations overactivated 
      mTORC1 and inhibited mTORC2 activity. This control process involved the 
      activation of ERK1/2, which promoted the inhibition of TSC2 and activation of 
      S6K. Furthermore, S6K was crucial to promoting the over activation of mTORC1 and 
      inhibition of mTORC2. Megalin expression at the luminal membrane is reduced by 
      high concentrations of albumin. In addition, knockdown of megalin mimicked all 
      the effects of pathophysiologic albumin concentrations, which disrupt normal 
      signal transduction pathways and lead to an overactivation of mTORC1 and 
      inhibition of mTORC2. These data provide new perspectives for understanding the 
      molecular mechanisms behind the effects of albumin on the progression of renal 
      disease.
CI  - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Peruchetti, Diogo B
AU  - Peruchetti DB
AD  - From the Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio 
      de Janeiro, Rio de Janeiro 21941-902, Brazil and Department of Physiology, School 
      of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205.
FAU - Cheng, Jie
AU  - Cheng J
AD  - Department of Physiology, School of Medicine, The Johns Hopkins University, 
      Baltimore, Maryland 21205.
FAU - Caruso-Neves, Celso
AU  - Caruso-Neves C
AD  - From the Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio 
      de Janeiro, Rio de Janeiro 21941-902, Brazil and.
FAU - Guggino, William B
AU  - Guggino WB
AD  - Department of Physiology, School of Medicine, The Johns Hopkins University, 
      Baltimore, Maryland 21205 wguggino@jhmi.edu.
LA  - eng
GR  - P30 DK089502/DK/NIDDK NIH HHS/United States
GR  - R01 DK032753/DK/NIDDK NIH HHS/United States
GR  - DK032753/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140501
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Albumins)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-2)
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 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Albumins/pharmacology
MH  - Albuminuria/*metabolism
MH  - Animals
MH  - Cell Line
MH  - Epithelial Cells/drug effects/metabolism
MH  - Kidney Tubules, Proximal/cytology/*metabolism
MH  - Low Density Lipoprotein Receptor-Related Protein-2/genetics/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Multiprotein Complexes/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Swine
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC4059122
OTO - NOTNLM
OT  - Albumin
OT  - Cell Signaling
OT  - Epithelium
OT  - Receptor Regulation
OT  - mTOR Complex (mTORC)
EDAT- 2014/05/03 06:00
MHDA- 2014/10/25 06:00
PMCR- 2015/06/13
CRDT- 2014/05/03 06:00
PHST- 2014/05/03 06:00 [entrez]
PHST- 2014/05/03 06:00 [pubmed]
PHST- 2014/10/25 06:00 [medline]
PHST- 2015/06/13 00:00 [pmc-release]
AID - S0021-9258(20)40651-9 [pii]
AID - M114.549717 [pii]
AID - 10.1074/jbc.M114.549717 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Jun 13;289(24):16790-801. doi: 10.1074/jbc.M114.549717. Epub 
      2014 May 1.