hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase

Maya P. Byfield, James T. Murray, Jonathan M. Backer

Research output: Contribution to journalArticle

403 Citations (Scopus)

Abstract

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 PI(3)P, 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.

Original languageEnglish (US)
Pages (from-to)33076-33082
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number38
DOIs
StatePublished - Sep 23 2005

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70-kDa Ribosomal Protein S6 Kinases
Sirolimus
Nutrients
Phosphotransferases
Chemical activation
Insulin
Lipids
Food
Phosphorylation
Amino Acids
Glucose
Small Interfering RNA
Class III Phosphatidylinositol 3-Kinases
Phosphatidylinositol 3-Kinase
AMP-Activated Protein Kinases
Autophagy
Microinjections
Starvation
Phosphatidylinositols
Anti-Idiotypic Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. / Byfield, Maya P.; Murray, James T.; Backer, Jonathan M.

In: Journal of Biological Chemistry, Vol. 280, No. 38, 23.09.2005, p. 33076-33082.

Research output: Contribution to journalArticle

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