hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling

https://doi.org/10.1016/j.ceb.2007.02.019Get rights and content

Recent studies have shown that the nutrient input to the mTOR Complex1/S6K1 signaling pathway is mediated by class 3 PI3K or hVps34, the oldest member of the PI3K family. Moreover, studies to date would suggest that during the evolution of multicellular organisms this ancient branch of the pathway was merged with the growth-factor-hormone-controlled class 1 PI3K pathway at the level of mTOR Complex1 to control the development and growth of the organism. However, hVps34 also plays a role in the regulation of macroautophagy — the mechanism by which cells generate nutrients, such as amino acids, through the degradation of intracellular complexes, including mitochondria and ribosomes. These functions of hVps34 initially appear contradictory, since increased mTOR Complex1 activation is triggered by increased amino acid levels, while autophagy is triggered when cells are faced with amino acid deprivation.

Introduction

It has been known for nearly a decade that the mammalian target of rapamycin (mTOR) Complex1 is exquisitely sensitive to nutrients. However, there has been little understanding of the underlying mechanisms which mediate this response, despite an increasing awareness of the importance of this pathway in metabolic syndromes such as diabetes, obesity and cancer. Here we review the recent finding that hVps34 mediates nutrient signaling to mTOR. We also discuss a potential framework to rationalize the distinct roles played by hVps34 in the control of growth versus autophagy.

Section snippets

mTOR Complex1/S6K1

mTOR and its downstream effector S6 kinase 1 (S6K1), as well as initiation factor 4E binding protein (4E-BP1), have emerged as critical signaling components in the development, differentiation and growth of the organism [1], as well as in the maintenance of normal metabolic homeostasis [2, 3]. In the case of S6K1, mTOR appears to influence these processes largely at the level of protein synthesis, through S6K1 phosphorylation of target proteins, such as ribosomal protein S6 [4], elongation

hVps34 and mTOR

The link between hVps34 and mTOR Complex1 signaling emerged independently in studies designed to elucidate the mechanism by which nutrient input, particularly of amino acids and glucose, leads to increased S6K1 T389 phosphorylation as a readout of mTOR Complex1 activation [34•, 35••]. Initially it was presumed that amino acids affected mTOR Complex1/S6K1 by acting through the generic class 1 PI3K branch of this pathway [35••]. In the absence of TSC1/TSC2, although mTOR Complex1/S6K1 activation

Autophagy and endosome signaling

hVps34 is known to play a critical role in autophagy, and has been shown to directly interact with the autophagic gene beclin. Beclin was first identified as a Bcl-2-interacting protein in a yeast two-hybrid screen [61]. Subsequently it has been shown to be a haploinsufficient tumor suppressor gene [62, 63], and it has been demonstrated that overexpression of Bcl-2 disrupts the hVps34–beclin interaction [64]. Moreover, it is hypothesized that, in a nutrient-replete setting, Bcl-2 inhibits

Future perspectives

Given the ability of mTOR Complex1 to suppress autophagy, and the importance of both endosome trafficking and autophagy to the malignant phenotype, it will be critical to identify the mechanisms by which these two pathways interact at the intracellular level. Currently, hVps34 and hVps15 are the only known components of the pathway linking nutrient input to mTOR Complex1 activation. Thus, identifying the upstream and downstream elements of this pathway will be critical to deciphering the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

We thank M Daston for editing and members of Kozma/Thomas laboratory for discussions and insights concerning this review. GT is supported by a U01 grant of the Mouse Models of Human Cancer Consortium (CA-84292-06) and an R01 grant (DK-73802-01) from the NIH. SK is supported by a R01 grant (CA-120475-01) from the NIH.

References (75)

  • D.R. Alessi et al.

    Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha

    Current Biology

    (1997)
  • M. Nellist et al.

    Identification and characterization of the interaction between tuberin and 14-3-3ζ

    J Biol Chem

    (2002)
  • Y. Li et al.

    Regulation of TSC2 by 14-3-3 binding

    J Biol Chem

    (2002)
  • B.D. Manning et al.

    Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway

    Mol Cell

    (2002)
  • K. Yamagata et al.

    rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein

    J Biol Chem

    (1994)
  • A. Garami et al.

    Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2

    Mol Cell

    (2003)
  • X. Long et al.

    Rheb binds and regulates the mTOR kinase

    Curr Biol

    (2005)
  • M.P. Byfield et al.

    hVps34 is a nutrient-regulated lipid kinase required for activation of p70 s6 kinase

    J Biol Chem

    (2005)
  • G. Xu et al.

    Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic β-cells. A possible role in protein translation and mitogenic signaling

    J Biol Chem

    (1998)
  • Y. Iiboshi et al.

    Amino acid-dependent control of p70(s6k). Involvement of tRNA aminoacylation in the regulation

    J Biol Chem

    (1999)
  • S.R. Kimball et al.

    Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin

    Curr Opin Clin Nutr Metab Care

    (2004)
  • E.S. Lee et al.

    Synergistic effect of alanine and glycine on bovine embryos cultured in a chemically defined medium and amino acid uptake by vitro-produced bovine morulae and blastocysts

    Biol Reprod

    (1996)
  • A. Kihara et al.

    Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network

    EMBO Rep

    (2001)
  • E.M. Smith et al.

    The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses

    J Biol Chem

    (2005)
  • X.H. Liang et al.

    Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein

    J Virol

    (1998)
  • T. Proikas-Cezanne et al.

    WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy

    Oncogene

    (2004)
  • A. Simonsen et al.

    EEA1 links PI(3)K function to Rab5 regulation of endosome fusion

    Nature

    (1998)
  • B.B. Kahn et al.

    mTOR tells the brain that the body is hungry

    Nat Med

    (2006)
  • I. Ruvinsky et al.

    Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis

    Genes Dev

    (2005)
  • X. Wang et al.

    Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase

    Embo J

    (2001)
  • B. Raught et al.

    Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases

    Embo J

    (2004)
  • N.V. Dorrello et al.

    S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth

    Science

    (2006)
  • M. Krebs

    Amino acid-dependent modulation of glucose metabolism in humans

    Eur J Clin Invest

    (2005)
  • S. Faivre et al.

    Current development of mTOR inhibitors as anticancer agents

    Nat Rev Drug Discov

    (2006)
  • E. Jacinto et al.

    Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

    Nat Cell Biol

    (2004)
  • J. Yang et al.

    Leucine regulation of glucokinase and ATP synthase sensitizes glucose-induced insulin secretion in pancreatic β-cells

    Diabetes

    (2006)
  • D.D. Sarbassov et al.

    Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

    Science

    (2005)
  • Cited by (93)

    View all citing articles on Scopus
    View full text