PMID- 23836898
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20220409
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 33
DP  - 2013 Aug 16
TI  - Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association 
      to protect cardiomyocytes.
PG  - 23798-806
LID - 10.1074/jbc.M113.482026 [doi]
AB  - Hexokinase II (HK-II) is an enzyme that catalyzes the first step in glycolysis 
      and localizes not only in the cytosol but also at mitochondria. Akt, activated by 
      insulin-like growth factor 1 (IGF-1) treatment in neonatal rat ventricular 
      myocytes, translocates to mitochondria and increases mitochondrial HK-II binding. 
      Expression of an HK-II-dissociating peptide diminished IGF-1-induced increases in 
      mitochondrial HK-II as well as protection against hydrogen peroxide treatment, 
      suggesting an important role of mitochondrial HK-II in IGF-1/Akt-mediated 
      protection. We hypothesized, on the basis of an Akt phosphorylation consensus 
      sequence present in HK-II, that Thr-473 is the target of Akt kinase activity. 
      Indeed, recombinant kinase-active Akt robustly phosphorylates WT HK-II, but not 
      Thr-473 mutants. Phosphomimetic (T473D)HK-II, but not non-phosphorylatable 
      (T473A)HK-II, constitutively increased mitochondrial binding compared with WT 
      HK-II and concomitantly confers greater protection against hydrogen peroxide. 
      Glucose 6-phosphate (G-6P), a product of the catalytic activity of HK-II, is well 
      known to dissociate HK-II from mitochondria. Addition of G-6P to isolated 
      mitochondria dose-dependently dissociates WT HK-II, and this response is 
      inhibited significantly in mitochondria isolated from cardiomyocytes expressing 
      T473D HK-II. Pretreatment with IGF-1 also inhibits G-6P-induced overexpressed or 
      endogenous HK-II dissociation, and this response was blocked by Akt inhibition. 
      These results show that Akt phosphorylation of HK-II at Thr-473 is responsible 
      for the Akt-mediated increase in HK-II binding to mitochondria. This increase is, 
      at least in part, due to the decreased sensitivity to G-6P-induced dissociation. 
      Thus, phosphorylation-mediated regulation of mitochondrial HK-II would be a 
      critical component of the protective effect of Akt.
FAU - Roberts, David J
AU  - Roberts DJ
AD  - Department of Pharmacology, University of California San Diego, La Jolla, 
      California 92093, USA.
FAU - Tan-Sah, Valerie P
AU  - Tan-Sah VP
FAU - Smith, Jeffery M
AU  - Smith JM
FAU - Miyamoto, Shigeki
AU  - Miyamoto S
LA  - eng
GR  - R01 HL097037/HL/NHLBI NIH HHS/United States
GR  - R56 HL097037/HL/NHLBI NIH HHS/United States
GR  - HL097037/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130708
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Mutant Proteins)
RN  - 1114-81-4 (Phosphothreonine)
RN  - 56-73-5 (Glucose-6-Phosphate)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
EIN - J Biol Chem. 2013 Nov 8;288(45):32638
MH  - Animals
MH  - Animals, Newborn
MH  - *Cytoprotection/drug effects
MH  - Enzyme Activation/drug effects
MH  - Glucose-6-Phosphate/pharmacology
MH  - Hexokinase/*metabolism
MH  - Hydrogen Peroxide/pharmacology
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Mice
MH  - Mitochondria, Heart/drug effects/*enzymology
MH  - Models, Biological
MH  - Mutant Proteins/metabolism
MH  - Myocytes, Cardiac/*cytology/drug effects/*enzymology
MH  - Phosphorylation/drug effects
MH  - Phosphothreonine/*metabolism
MH  - Protein Binding/drug effects
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC3745326
OTO - NOTNLM
OT  - Akt PKB
OT  - Cardiomyocytes
OT  - Cell Death
OT  - Glucose 6-Phosphate
OT  - Hexokinase
OT  - Insulin-like Growth Factor (IGF)
OT  - Mitochondria
OT  - Phosphorylation
EDAT- 2013/07/10 06:00
MHDA- 2013/12/16 06:00
PMCR- 2013/07/08
CRDT- 2013/07/10 06:00
PHST- 2013/07/10 06:00 [entrez]
PHST- 2013/07/10 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2013/07/08 00:00 [pmc-release]
AID - S0021-9258(20)45270-6 [pii]
AID - M113.482026 [pii]
AID - 10.1074/jbc.M113.482026 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Aug 16;288(33):23798-806. doi: 10.1074/jbc.M113.482026. Epub 
      2013 Jul 8.