View source for TOR signaling cascade ; GO:0031929

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==TOR SIGNALING IN GO==

GO term (April 2013):

 TOR signaling cascade ; [http://www.ebi.ac.uk/QuickGO/GTerm?id=GO:0031929 GO:0031929]  
 A series of molecular signals mediated by TOR (Target of rapamycin) proteins, members of the phosphoinositide (PI) 3-kinase related kinase
 (PIKK) family that act as serine/threonine kinases in response to nutrient availability or growth factors.
 is_a: GO:0035556 ! intracellular signal transduction

 InterPro Mappings: 
 [http://www.ebi.ac.uk/interpro/entry/IPR004083 Raptor and orthologs]
 [http://www.ebi.ac.uk/interpro/entry/IPR027204 Stm1]
 [http://www.ebi.ac.uk/interpro/entry/IPR027466 Raptor and orthologs]

  TOR signaling cascade ; GO:0031929
  --[REG]regulation of TOR signaling cascade ; GO:0032006
  ---[ISA]negative regulation of TOR signaling cascade ; GO:0032007
  ---[ISA]positive regulation of TOR signaling cascade ; GO:0032008

==TOR SIGNALING OVERVIEW==

mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription [http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin]

[[File:TORsignaling.jpg]]

image taken from PMID 16469695



==mTOR COMPLEXES==

mTOR is the catalytic subunit of two molecular complexes: mTORC1 and mTORC2. PMID 22457327

*'''mTOR Complex 1 (mTORC1)''' 
**mTOR
**regulatory-associated protein of mTOR (Raptor)
**mammalian lethal with SEC13 protein 8 (MLST8)
**PRAS40 and DEPTOR (recently identified)

*'''mTOR Complex 2 (mTORC2)''' 
**mTOR
**rapamycin-insensitive companion of mTOR (Rictor)
**GβL,
**mammalian stress-activated protein kinase interacting protein 1 (mSIN1)

==ACTIVATION OF TOR==

Four major inputs have been implicated in TOR signaling: growth factors, nutrients, energy, and stress.


===GROWTH FACTOR ACTIVATION OF TOR===

TOR is activated by INACTIVATION of TSC1/TSC2, and by ACTIVATION of Rheb (See Figure above)

#Rheb binds to mTOR to activate it in a GTP-dependent manner.
#Rheb is kept INACTIVE by a heterodimeric complex of TSC1/TSC2: TSC2 acts as a GAP (GTPase-activating protein) for the small GTPase Rheb.
#TSC2 is phosphorylated and functionally INACTIVATED by Akt in response to insulin (TSC2 may also be phosphorylated and inactivated by other kinases).


===NUTRIENT ACTIVATION OF TOR===

* Amino acids have been proposed to activate mTORC1 via inhibition of TSC1-TSC2 or, alternatively, via stimulation of Rheb.


===STRESS INACTIVATION OF TOR===

* Upon hypoxia (low O2), TOR signaling is inhibited and protein synthesis is thereby downregulated.




==DOWNSTREAM TARGETS OF TOR==

* mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 to activate AKT (acts as the elusive PDK2). AKT is involved in growth control.


===TRANSLATION TARGETS===

* mTORC1 regulates translation by phosphorylating S6K1: Activated S6K1 phosphorylates the 40S ribosomal protein S6 to stimulate translation.
* mTORC1 phosphorylates 4E-BP. Phosphorylated 4E-BP1 releases eIF4E, which is then free to associate with eIF4G to stimulate translation initiation.


mTORC1 also targets GPs involved in cell growth, transcription, ribosome biogenesis etc.

mTORC2 has roles in the actin cytoskeleton.



==QUESTIONS==

*What is included in TOR signaling cascade? 
**Everything ABOVE AND BELOW TOR? 
OR
**Does the cascade START with members of the TOR complex. With upstream signaling molecules REGULATING the pathway?


==GENE PRODUCTS==

When deciding the start and end points, need to consider which of the following proteins are participants in the pathway, and which REGULATE the pathway?

* '''mTOR''' (most definitely a PARTICIPANT in the pathway.
* '''Raptor''' (member of mTORC1 complex): PARTICIPANT in the pathway
* '''Rictor''' (member of mTORC2 complex): PARTICIPANT in the pathway
* '''Rheb''' (activator of the mTORC1 complex)
* '''TSC1/TSC2''' (NEGATIVELY regulates mTOR)
* '''AKT''' (Acts upstream of mTOR, to ACTIVATE mTOR). Also a downstream substrate of mTOR.
* '''PI3K''' (acts upstream of AKT)
* '''Insulin Receptor''' (receives the initial signal)
* '''Insulin''' (signal)
* '''S6K''' (Downstream kinase target of mTOR)
* '''4E-BP''' (Downstream kinase target of mTOR: phosphorylation INACTIVATES 4E-BP, to release its translation binding partner)

==REFEFENCES==

[http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin Wikipedia]

[http://www.cellsignal.com/reference/pathway/mTor.html TOR Signaling]

PMID 16469695

PMID 12372295

PMID 22457327


[[Category:Ontology]]