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Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
mTORC2 targets AGC kinases through Sin1-dependent recruitment
Angus J M Cameron1, Mark D Linch, Adrian T Saurin
1Protein Phosphorylation Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
The Biochemical Journal
|August 3, 2011
Summary
The target of rapamycin complex 2 (mTORC2) subunit Sin1 acts as a scaffold, enabling mTORC2 to phosphorylate protein kinase C (PKC) and protein kinase B (PKB)/Akt, crucial for cell growth and proliferation.
Area of Science:
- Cell biology
- Molecular signaling
- Biochemistry
Background:
- The target of rapamycin (TOR) pathway regulates cell growth and metabolism.
- Mammalian TOR exists as two complexes, mTORC1 and mTORC2, with distinct functions.
- The molecular mechanisms and therapeutic importance of mTORC2 are not fully understood.
Purpose of the Study:
- To elucidate the molecular role of mTORC2 components.
- To investigate the interaction between mTORC2 and protein kinase C (PKC).
- To determine the function of mTORC2 in cell proliferation.
Main Methods:
- Identified Sin1 as a direct binding partner of the PKCε kinase domain.
- Mapped the Sin1-PKC interaction site.
- Utilized inducible expression of Sin1 mutants to disrupt mTORC2 function.
- Assessed phosphorylation of PKC, PKB/Akt, and p70S6K.
Main Results:
- Sin1 directly binds to PKCε, facilitating PKC phosphorylation by mTORC2.
- Disruption of Sin1-PKC interaction impairs mTORC2-mediated phosphorylation of PKC and PKB/Akt.
- mTORC1 substrate p70S6K phosphorylation remains unaffected.
- Selective mTORC2 inhibition demonstrates its critical role in 3D cell proliferation.
Conclusions:
- Sin1 acts as a selectivity adaptor, recruiting substrates like PKC to mTORC2.
- mTORC2 is essential for PKC and PKB/Akt phosphorylation.
- Targeting mTORC2, particularly via Sin1, is a promising strategy for controlling cell proliferation.
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