PMID- 16049009
OWN - NLM
STAT- MEDLINE
DCOM- 20051128
LR  - 20230815
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 38
DP  - 2005 Sep 23
TI  - hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 
      kinase.
PG  - 33076-82
AB  - Mammalian cells respond to nutrient deprivation by inhibiting energy consuming 
      processes, such as proliferation and protein synthesis, and by stimulating 
      catabolic processes, such as autophagy. p70 S6 kinase (S6K1) plays a central role 
      during nutritional regulation of translation. S6K1 is activated by growth factors 
      such as insulin, and by mammalian target of rapamycin (mTOR), which is itself 
      regulated by amino acids. The Class IA phosphatidylinositol (PI) 3-kinase plays a 
      well recognized role in the regulation of S6K1. We now present evidence that the 
      Class III PI 3-kinase, hVps34, also regulates S6K1, and is a critical component 
      of the nutrient sensing apparatus. Overexpression of hVps34 or the associated 
      hVps15 kinase activates S6K1, and insulin stimulation of S6K1 is blocked by 
      microinjection of inhibitory anti-hVps34 antibodies, overexpression of a FYVE 
      domain construct that sequesters the hVps34 product PI3P, or small interfering 
      RNA-mediated knock-down of hVps34. hVps34 is not part of the insulin input to 
      S6K1, as it is not stimulated by insulin, and inhibition of hVps34 has no effect 
      on phosphorylation of Akt or TSC2 in insulin-stimulated cells. However, hVps34 is 
      inhibited by amino acid or glucose starvation, suggesting that it lies on the 
      nutrient-regulated pathway to S6K1. Consistent with this, hVps34 is also 
      inhibited by activation of the AMP-activated kinase, which inhibits mTOR/S6K1 in 
      glucose-starved cells. hVps34 appears to lie upstream of mTOR, as small 
      interfering RNA knock-down of hVps34 inhibits the phosphorylation of another mTOR 
      substrate, eIF4E-binding protein-1 (4EBP1). Our data suggest that hVps34 is a 
      nutrient-regulated lipid kinase that integrates amino acid and glucose inputs to 
      mTOR and S6K1.
FAU - Byfield, Maya P
AU  - Byfield MP
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, 
      New York 10461, USA.
FAU - Murray, James T
AU  - Murray JT
FAU - Backer, Jonathan M
AU  - Backer JM
LA  - eng
GR  - T32 GM07491/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050727
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (RNA, Small Interfering)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Animals
MH  - CHO Cells
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cricetinae
MH  - Enzyme Activation
MH  - Glucose/metabolism
MH  - Green Fluorescent Proteins/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Insulin/metabolism
MH  - Models, Biological
MH  - Multienzyme Complexes/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism/*physiology
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Protein Biosynthesis
MH  - Protein Conformation
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein Structure, Tertiary
MH  - RNA, Small Interfering/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
EDAT- 2005/07/29 09:00
MHDA- 2005/12/13 09:00
CRDT- 2005/07/29 09:00
PHST- 2005/07/29 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/07/29 09:00 [entrez]
AID - S0021-9258(20)79167-2 [pii]
AID - 10.1074/jbc.M507201200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Sep 23;280(38):33076-82. doi: 10.1074/jbc.M507201200. Epub 2005 
      Jul 27.