mTOR
Transcription Factors

Author: Gianpiero Pescarmona
Date: 04/11/2007

Description

DEFINITION

The Mammalian target of rapamycin (mTor) (or FK506 binding protein 12-rapamycin associated protein 1: FRAP1) is a protein which in humans is encoded by the FRAP1 gene. mTOR is a serine/threonine protein kinase with pleiotropic functions that belongs to the phosphatidylinositol 3-kinase-related kinase protein family.

Bella tesina 2007

THE GENE

DatabaseLink
WikigenesmTOR
GeneCards"mTOR":
Your Favorite Gene Sigma"mTOR":

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage

SYNTHESIS AND TURNOVER

mRNA synthesis

mTOR mRNA Tissue expression

protein synthesis

mTOR diet

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,

Click to see interactive mTOR signaling pathway Diagrams of PI3K/Akt/mTOR Signaling Pathway

biological function

mTOR is the Kinase subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals.

mTORC1mTORC2
mTOR catalytic subunitmTOR catalytic subunit
mLST8mLST8
DeptorDeptor
Rictor
mSIN1
mLST8

and at least five accessory proteins. , , and Protor are unique subunits of mTORC2. In contrast, are shared subunits of mTORC1 and mTORC2. Rictor, mSIN1, and (in addition to mTOR) are the core essential components of the complex and are required for maintaining structural integrity. In contrast, mTORC2 activity does not require Deptor and Protor, which may function as regulatory proteins. Deptor seems to negatively regulate mTORC2, whereas the function of Protor is unknown. (

mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer

Abstract
Regulation of growth and proliferation in higher eukaryotic cells results from an integration of nutritional, energy, and mitogenic signals. Biochemical processes underlying cell growth and proliferation are governed by the phosphatidylinositol 3-kinase (PI3K) and target of rapamycin (TOR) signaling pathways. The importance of the interplay between these two pathways is underscored by the discovery that the TOR inhibitor rapamycin is effective against tumors caused by misregulation of the PI3K pathway. We review here recent data concerning the convergence of the PI3K and TOR pathways, the role of these pathways in cell growth and proliferation, and the regulation of growth by downstream TOR targets.

Full Text

Proto-oncogenes that affect the mTOR Complex1–S6K1 pathway

GeneSyndromeMolecular function
PI3KOvarian and gastrointestinal cancerActivates PKB/Akt via PIP3
PKB/AktBreast and ovarian cancer Activates mTOR Complex1
RASPancreatic and colon cancerActivates PI3K

mTOR1 and mTOR2 2007

The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism.

Two structurally and functionally distinct mTOR-containing multiprotein complexes have been identified. mTOR exists in two complexes: mTOR Complex1, which is rapamycin-sensitive and phosphorylates S6K1 and initiation factor 4E binding proteins (4E-BPs), and mTOR Complex2, which is rapamycin-insensitive and phosphorylates protein kinase B (PKB, also known as Akt).

Tuberous sclerosis complex: linking cancer to metabolism. 2010
Trends Mol Med. 2010 Jun 2. [Epub ahead of print]
Mieulet V, Lamb RF.

The TSC1/TSC2 tumor-suppressor complex regulates cell growth via controlling the mTOR (mammalian target of rapamycin) signaling pathway, which contributes to several disease processes, including cancer and diabetes. Abnormal activation of mTOR uncouples anabolic cell growth processes such as protein and lipid synthesis from external growth factor or nutrient cues. However, abnormal activation of mTOR upon loss of TSC1/TSC2 complex function is now known to lead to compensatory mechanisms that restrict the development of malignant tumors . The rare occurrence of complete loss of TSC1/TSC2 function in human tumors suggests that retaining growth suppressor activity might be beneficial during tumour evolution, perhaps by promoting survival when cells grow in a nutrient-limited environment. Copyright © 2010 Elsevier Ltd. All rights reserved.

Upstream mTOR (FRAP1)

Leucine

This model (from Reynolds et al. 2007) shows postulated roles for three types of transporter (right-hand side of figure) in regulating the kinase TOR, which is central to cell growth pathways. General amino-acid transporters (AAT) may deliver nutrients; CD98-related transporters are specifically involved in delivery of leucine (through system L) to intracellular sensors; additionally, there is a distinct role of PAT-related transporters in activating insulin signalling pathways, possibly by protein–protein interactions that may depend on intracellular trafficking of this class of transporter. Note the general significance of such interactions, both in normal and abnormal physiology, as indicated by the number of potential ‘disease' phenotypes (indicated in capitals). The left-hand side of the figure outlines the classical insulin regulated signalling pathways. inR, insulin receptor; TOR, target of rapamycin; PAT, proton-coupled amino acid transporter.

Facts, fantasies and fun in epithelial physiology 2008

mTOR patway is down-regulated by AMPK (activated by AMP, Metformin, AICAR)

AMPK activation depends on:

TSC1/2, rheb, and AMPK are upstream regulators of mTOR (FRAP1). TSC1 and TSC2 receive input from several signalling pathways, including the PI3K–Akt (insulin-signalling) pathway, the ERK1/2 pathway, the p38MAPK–MK2 pathway and the LKB1–AMPK (energy-sensing) pathway, as well as GSK3β. Also, there is probably direct input from signalling in response to hypoxia.

Downstream mTOR (FRAP1)

In response to these signals, TSC1–2 acts as a GTPase-activating protein (GAP) for Rheb, which, in turn, regulates mTOR. Activated mTOR has many main downstream targets, RPS6KB1 (S6K1), 4E-BP1 (cell growth and proliferation), ATG1 (autophagocytosis) and HIF.

Metabolic pathways

The mammalian target of rapamycin (mTOR or FRAP1) and its effector, S6 kinase 1 (S6K1 or RPS6KB1), lie at the crossroads of a nutrient-hormonal signaling network that is involved in specific pathological responses, including obesity, diabetes and cancer.

Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrient and energy inputs. Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues.

  • Enzymes
DatabaseLink
BRENDA - The Comprehensive Enzyme Information System"URL":
KEGG Pathways"URL":
Human Metabolome Database"URL":
  • Cell signaling and Ligand transport
  • Structural proteins

REGULATION

DIAGNOSTIC USE

Participation of mTOR Complex 1 in TLR2 and TLR4 Induced Neutrophil Activation and Acute Lung Injury. 2009

Comments
2012-04-15T10:23:53 - jason sun

c-kit

2008-04-17T13:16:08 - Gianpiero Pescarmona

A role for Methionine?

file Excel

Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways, 2011

mTor site

Quertle: mTor and b cells

mTor Protocols

Model of Insulin/mTor interaction 2009

Roma, 25 mar. (Adnkronos Salute) - Scoperto un nuovo meccanismo di controllo del metabolismo cellulare, che vede al centro due proteine: mTor e Ambra1. Grazie alla scoperta di un pool di ricercatori dell'Università Roma Tor Vergata e Fondazione Santa Lucia, finanziata da Airc, Telethon e Fism, sarà dunque possibile mettere a punto nuove strategie farmacologiche in grado di controllare le scelte metaboliche e dunque il processo di autofagìa delle nostre cellule in diverse patologie. Lo studio è stato appena pubblicato su 'Nature Cell Biology'.

Il gruppo di ricerca condotto da Francesco Cecconi del Dipartimento di Biologia dell'Università di Tor Vergata ha dunque svelato un meccanismo fondamentale nel controllo del metabolismo di ogni nostra cellula. Conoscere in dettaglio il modo in cui le cellule utilizzano i nutrienti e mobilizzano le loro risorse energetiche è di grande importanza in oncologia e nella lotta contro molte altre malattie (neurodegenerazioni, distrofie muscolari congenite, autoimmunità, oltre naturalmente alle malattie metaboliche, quali l'obesità o le malattie da accumulo lisosomiale). Le cellule tumorali, infatti, crescono velocemente utilizzando meccanismi alternativi per produrre energia e prediligendo il riciclaggio dei propri componenti anziché lo sfruttamento delle risorse esterne. Mettono in pratica, quindi, un attento piano di "risparmio energetico" per riprodursi a lungo, reagire alla risposta del nostro sistema immunitario ed invadere i nostri tessuti.

Questo processo prende il nome di autofagìa (dal greco autòs fagèin, mangio me stesso). Con lo stesso sistema, si pensa che spesso le cellule tumorali sfuggano alle aggressioni della chemioterapia o dei nuovi farmaci biologici. I neuroni e le cellule muscolari, invece, ricorrono alla stessa attività metabolica alternativa per 'ripulirsi' da sostanze tossiche o da organuli difettosi e, quando il meccanismo di ripulitura si inceppa, vanno incontro a degenerazione, come avviene ad esempio nel morbo di Parkinson o nella distrofia di Bethlem. L'autofagìa può avere, dunque, per la salute umana, ruoli negativi come nei tumori, oppure positivi, come nelle malattie degenerative, a seconda delle circostanze.

Molecola chiave nella regolazione metabolica di tutte le nostre cellule è la grande proteina mTor, ossia il principale regolatore di come e quando le cellule producono altre proteine. Questa proteina integra infatti tutte le comunicazioni che provengono dai nutrienti e dai fattori di crescita, e funge da punto di connessione fra i segnali cellulari per controllare crescita, metabolismo, e persino longevità nelle cellule sane.

Francesca Nazio e i ricercatori diretti da Cecconi hanno scoperto che mTor - definita pochi mesi fa il gene 'master' della vita dagli scienziati - quando la cellula è in buona salute e i nutrienti a sua disposizione abbondano, blocca ogni attività di risparmio energetico nella cellula stessa, mediante la specifica regolazione biochimica della proteina Ambra1, limitando, in sostanza, il ricorso della cellula stessa a vie metaboliche alternative. Se invece la cellula è sottoposta a stress e i nutrienti scarseggiano, questo blocco è rimosso, mTor smette di funzionare e Ambra1 si attiva sostenendo così l'autofagìa come sistema di riequilibrio energetico. I ricercatori hanno anche scoperto come Ambra1 regoli l'autofagia: Ambra1 modifica la proteina Ulk1, stabilizzandola, affinché stimoli e mantenga il processo autofagico in funzione.

Questo meccanismo è di grande importanza perché "è difficile modulare i davvero pochi bersagli molecolari di mTor, sinora identificati nella cellula per controllare il metabolismo cellullare. Si può prevedere, quindi - concludono i ricercatori - che questa scoperta consenta la messa a punto di nuove strategie farmacologiche mirate a modulare Ambra1 e mTor, e capaci di controllare le scelte metaboliche delle nostre cellule in numerose condizioni patologiche, anche molto diverse fra loro".

mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6.C, 2013

Autophagy process is associated with anti-neoplastic function. 2011

p62, Ras, and autophagy. Under conditions of low autophagy, p62 accumulates and activates inflammation via NF-κB, and increases the expression of ROS scavengers via NF-κB and Nrf2. The net effect is enhanced tumorigenesis.

Autophagy in the Cellular Energetic Balance. 2011

Different Catabolic Pathways Converge in LysosomesMacroautophagy contributes to the delivery of proteins, lipid stores, and glycogen for breakdown into lysosomes. The constituent components of these macromolecules exit the lysosome and become available for production of energy. In the case of protein breakdown, the resulting amino acids may have less energetic value and be preferentially utilized for the synthesis of new proteins. Levels of amino acids, free fatty acids, and sugars circulating in blood or in the extracellular media have a direct impact on intracellular macroautophagy.

.

.

p62, Ras, and autophagy. Under conditions of low autophagy, p62 accumulates and activates inflammation via NF-κB, and increases the expression of ROS scavengers via NF-κB and Nrf2. The net effect is enhanced tumorigenesis.

p62: a versatile multitasker takes on cancer, 2012

!http://download.cell.com/images/journalimages/1097-

2008-01-15T11:50:04 - Marcello Capella Federica DAmico

AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. (It is activated by high AMP/ATP ratio)

interaction between TSC and mTOR

p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway, 2011 FULLTEXT

Attachments
AddThis Social Bookmark Button