Elsevier

The Enzymes

Volume 28, 2010, Pages 21-48
The Enzymes

2 - The TSC1–TSC2 Complex: A Key Signal-Integrating Node Upstream of TOR

https://doi.org/10.1016/S1874-6047(10)28002-2Get rights and content

Publisher Summary

The complexity and breadth of the signaling network upstream of the TSC1 (hamartin)–TSC2 (tuberin) complex is a testament to the importance of proper regulation of mTORC1 in the tight control over cellular growth and proliferation. The TSC1–TSC2 complex negatively regulates TORC1 through its guanosine triphosphatase (GTPase)-activating protein (GAP) activity toward the small G-protein Ras homolog enriched in brain (Rheb), an essential activator of TORC1. In contrast, TORC2 in mammalian cells is positively regulated by the TSC1–TSC2 complex through both Rheb and TORC1-dependent and independent mechanisms. The regulatory relationship between the TSC1–TSC2 complex and TORC1 appears to be conserved in most eukaryotes, including species of yeast. Multisite phosphorylation of both TSC1 and TSC2 promotes or inhibits the ability of the complex to inhibit Rheb downstream of a wide variety of kinases and signaling pathways. Several of these pathways include important oncogene products and tumor suppressors that can promote inhibition of the TSC1–TSC2 complex and contribute to the aberrantly elevated levels of mTORC1 signaling detected in the majority of human cancers. Inactivating mutations in the TSC1 and TSC2 genes give rise to a multifaceted tumor syndrome known as “tuberous sclerosis complex.”

Section snippets

Abstract

The TSC1 (hamartin) and TSC2 (tuberin) proteins function as a heterodimer that integrates diverse extracellular and intracellular signals to regulate the two TOR complexes (TORC1 and TORC2; mTORC1 and mTORC2 in mammals) and the processes of cell growth and proliferation. The TSC1–TSC2 complex negatively regulates TORC1 through its GTPase-activating protein (GAP) activity toward the small G-protein Rheb (Ras homolog enriched in brain), an essential activator of TORC1. In contrast, TORC2 in

The TSC1–TSC2 Complex Negatively Regulates Growth and Proliferation

Since the genetic loss of TSC1 and TSC2 that underlies TSC results in tumor formation in multiple organs, these genes have long been classified as tumor suppressors. An important milestone in understanding the function of the TSC1–TSC2 complex came when its tumor suppressor activity was linked at the molecular level to the GAP domain of TSC2 30, 31 and to control over a basic physiological process—cell growth. Germline ablation of either Tsc1 or Tsc2 in rodents leads to embryonic lethality 32,

Upstream Regulation: The TSC1–TSC2 Complex Integrates Diverse Signals to Regulate mTORC1

As a critical upstream regulator of mTORC1, the TSC1–TSC2 complex has emerged as a signal-integrating hub that senses cell growth conditions. In general, conditions favorable to cell growth and proliferation inhibit the TSC1–TSC2 complex to activate Rheb and mTORC1, while poor growth conditions activate the TSC1–TSC2 complex to inhibit Rheb and mTORC1. Multisite phosphorylation of specific serine and threonine residues on TSC1 and TSC2 is the primary mechanism by which the complex senses these

Aberrant Inhibition of the TSC1–TSC2 Complex Leading to Activation of mTORC1 in the Majority of Human Tumors

The complexity and breadth of the signaling network upstream of the TSC1–TSC2 complex is a testament to the importance of proper regulation of mTORC1 in the tight control over cellular growth and proliferation. Aberrantly elevated mTORC1 signaling is detected in the majority of genetic tumor syndromes and sporadic cancers [132]. Several of the most commonly activated oncogene products and inactivated tumor suppressors lie upstream of the TSC1–TSC2 complex (Figure 2.6). Amplifications and

Important Outstanding Questions Concerning the TSC1–TSC2 Complex

The enormous increase in our understanding of the TSC1–TSC2 complex and upstream regulation of mTORC1 over the past decade raises several remaining fundamental questions. First, a comprehensive understanding of how phosphorylation regulates the complex needs to be developed. This should include determining the complete repertoire of kinases and pathways upstream of the complex, identifying all phosphorylation sites, and characterizing the hierarchy of the phosphorylation sites and how they

References (134)

  • A. Lupas

    Prediction and analysis of coiled-coil structures

    Methods Enzymol

    (1996)
  • D.J. Noonan et al.

    A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis

    Arch Biochem Biophys

    (2002)
  • N. Ito et al.

    gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle

    Cell

    (1999)
  • N. Tapon et al.

    The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation

    Cell

    (2001)
  • E.A. Goncharova et al.

    Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)

    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.R. Tee et al.

    Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb

    Curr Biol

    (2003)
  • A.F. Castro et al.

    Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner

    J Biol Chem

    (2003)
  • 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)
  • Y. Sancak et al.

    PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase

    Mol Cell

    (2007)
  • T. Sato et al.

    Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein

    J Biol Chem

    (2009)
  • A.P. Tabancay et al.

    Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K

    J Biol Chem

    (2003)
  • A.R. Tee et al.

    Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1

    FEBS Lett

    (2005)
  • R. Wienecke et al.

    Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity

    J Biol Chem

    (1995)
  • G.H. Xiao et al.

    The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis

    J Biol Chem

    (1997)
  • T. Brinkmann et al.

    Rap-specific GTPase activating protein follows an alternative mechanism

    J Biol Chem

    (2002)
  • P.S. Gromov et al.

    A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb

    FEBS Lett

    (1995)
  • M. van Slegtenhorst et al.

    Tsc1+ and tsc2+ regulate arginine uptake and metabolism in Schizosaccharomyces pombe

    J Biol Chem

    (2004)
  • J. Urano et al.

    The Saccharomyces cerevisiae Rheb G-protein is involved in regulating canavanine resistance and arginine uptake

    J Biol Chem

    (2000)
  • P.J. Aspuria et al.

    The Rheb family of GTP-binding proteins

    Cell Signal

    (2004)
  • O.J. Shah et al.

    Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies

    Curr Biol

    (2004)
  • B.D. Manning et al.

    AKT/PKB signaling: navigating downstream

    Cell

    (2007)
  • H.C. Dan et al.

    Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin

    J Biol Chem

    (2002)
  • D.R. Plas et al.

    Akt activation promotes degradation of tuberin and FOXO3a via the proteasome

    J Biol Chem

    (2003)
  • M. Nellist et al.

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

    J Biol Chem

    (2002)
  • S.D. Shumway et al.

    14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin

    J Biol Chem

    (2003)
  • A.R. Tee et al.

    Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin

    J Biol Chem

    (2003)
  • L. Ma et al.

    Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis

    Cell

    (2005)
  • P.B. Crino et al.

    The tuberous sclerosis complex

    N Engl J Med

    (2006)
  • J.P. Osborne et al.

    Epidemiology of tuberous sclerosis

    Ann N Y Acad Sci

    (1991)
  • M. van Slegtenhorst et al.

    Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

    Science (New York, NY)

    (1997)
  • R.S. Kandt et al.

    Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease

    Nat Genet

    (1992)
  • E.C.T.S. Consortium

    Identification and characterization of the tuberous sclerosis gene on chromosome 16

    Cell

    (1993)
  • G.H. Xiao et al.

    Identification of tuberous sclerosis 2 messenger RNA splice variants that are conserved and differentially expressed in rat and human tissues

    Cell Growth Differ

    (1995)
  • H. Zhang et al.

    Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K–Akt signaling through downregulation of PDGFR

    J Clin Invest

    (2003)
  • T.L. Plank et al.

    Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles

    Cancer Res

    (1998)
  • M. van Slegtenhorst et al.

    Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products

    Hum Mol Genet

    (1998)
  • X. Gao et al.

    TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth

    Genes Dev

    (2001)
  • J. Hu et al.

    WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase

    Genes Dev

    (2008)
  • Cited by (0)

    View full text