The mTOR pathway is a central regulator of cell growth that couples the control of protein synthesis to the availability of growth factors, nutrients, and energy.
mTOR: A protein kinase involved in regulation of protein synthesis in response to growth factors, nutrients, and energy availability.
Components of the mTOR pathway: mTOR/Raptor complex, Rheb protein, eIF4EBP and Rbosomal S6 Kinase
Signals can be: growth factor stimulation, depletion of cellular energy stores etc
The mTOR protein kinase exists in two distinct complexes in cells:
mTOR/ rictor complex (mTOR is associated with rictor): Protein kinases that phosphorylates and activates Akt (refer Akt pathway)
mTOR/raptor complex (mTOR associated with raptor): They are activated downstream of Akt and functions to regulate cell size and controlling protein synthesis.
- Regulator protein for mTOR / raptor complex: Rheb protein (Ras-related GTP-binding protein)
(Rheb protein activate mTOR/raptor complex)
- Rheb protein is in turn regulated by the GTPase-activating protein complex TSC1/2.
(Active TSC1/2 complex inhibit Rheb)
TCS1/2 can be regulated by two protein kinases:
1) Akt: Activation of mTOR/ raptor in response to growth factor stimulation
2) AMP/ activated kinases (AMPK): AMPK senses the energy state of the cell and is activated by a high ratio of AMP to ATP.
TSC2 is also regulated by the availability of amino acids.
How the mTOR pathway is regulated by Akt (Activated by binding of growth factor to its receptor tyrosine kinase)
Once the protein kinase B (Akt) is activated via RTK signaling, it will phosphorylate and inhibit TSC1/2 complex. As a result the inhibitory effect of this complex on Rheb protein is removed and Rheb protein becomes active. Active Rheb protein inturn activates mTOR/raptor complex.
The mTOR/raptor complex phosphorylates at least two well-characterized targets that function to regulate protein synthesis: Ribosomal S6 kinase and eIF4E binding protein-1 (4E-BP1).
- S6 kinase controls translation by phosphorylating the ribosomal protein S6 as well as other proteins involved in translational regulation.
- Ribosomal S6 kinases (Rsks) are serine/threonine kinases also activated by MAPK/ERK pathway
What are elF4EBP?
- They are translation repressor protein.
- The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is responsible for recruitment of 40S ribosomal subunits to the 5′ end of mRNAs. Interaction of this protein with eIF4E inhibits translation initiation complex assembly and represses translation.
- This protein is phosphorylated in response to various signals.
Growth factor signal: elF4EBP is phosphorylated and inhibited by active mTOR/raptor complex (activation of cap-dependent mRNA translation)
Depletion of cellular energy stores: eIF4EBP is active (translation inhibition)
How the mTOR pathway regulated when cellular energy stores are depleted?
When cellular energy stores are depleted (ratio of AMP to ATP is high), AMPK phosphorylates TSC2, leading to inhibition of Rheb protein (mTOR/raptor kinase complex activator).
Once this protein is inhibited, it no longer activates mTOR/raptor complex. As a result two major translation repression events happens
- S6 kinase activity will not be stimulated and eIF4E binding protein remain bound to eIF4E
- Non phosphorylated eIF4EBP -1 bind to eIF4E and inhibit translation by interfering with the interaction of eIF4E with eIF4G
Rapamycin (antibiotic produced by certain fungi) is a specific inhibitor of the mTOR/raptor complex and is used as an immunosuppressive drug in organ transplants.