TOR signaling cascade ; GO:0031929

From GO Wiki
Revision as of 01:32, 24 April 2013 by Rfoulger (talk | contribs)

Jump to: navigation, search

Return to Signaling Main Page [[1]]


TOR SIGNALING

mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription [2]

TORsignaling.jpg

image taken from PMID 16469695


mTOR COMPLEXES

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

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:

  1. Rheb binds to mTOR to activate it in a GTP-dependent manner.
  2. Rheb is kept INACTIVE by a heterodimeric complex of TSC1/TSC2: TSC2 acts as a GAP (GTPase-activating protein) for the small GTPase Rheb.
  3. 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 TOR activity?


REFEFENCES

Wikipedia

PMID 16469695