Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2
The mechanistic target of rapamycin (mTOR) protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2 :: Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved among at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.
Authors
- Dibyendu Mondal (ORCID: https://orcid.org/0000-0002-5047-6985)
- Michelle J. Lee (ORCID: https://orcid.org/0009-0009-9122-335X)
- David M. Sabatini (ORCID: https://orcid.org/0000-0002-1446-7256)
- Philip A. Cole (ORCID: https://orcid.org/0000-0001-6873-7824)
- Brad A. Palanski (ORCID: https://orcid.org/0000-0002-4049-4274)
- Nathanael S. Gray (ORCID: https://orcid.org/0000-0001-5354-7403)
- Max L. Valenstein (ORCID: https://orcid.org/0000-0001-7616-0148)
- Nam Chu (ORCID: https://orcid.org/0000-0001-9717-5007)
- Brian J. Groendyke (ORCID: https://orcid.org/0000-0002-3860-8308)
- Jarrod A. Marto (ORCID: https://orcid.org/0000-0003-2086-1134)
- Andrej Săli (ORCID: https://orcid.org/0000-0003-0435-6197)
- Martin S. Taylor (ORCID: https://orcid.org/0000-0001-5824-142X)
- Timothy R. O’Meara (ORCID: https://orcid.org/0000-0002-3651-5167)
- Maximilian Wranik (ORCID: https://orcid.org/0000-0002-2482-0164)
- Bryant D. Miller (ORCID: https://orcid.org/0009-0006-9145-8499)
- Yi Shi (ORCID: https://orcid.org/0000-0002-2761-8324)
- Kacper B. Rogala (ORCID: https://orcid.org/0000-0001-5997-7770)
- Samantha Congreve (ORCID: https://orcid.org/0009-0001-5277-2235)
- Matthew Hancock (ORCID: https://orcid.org/0000-0001-9820-3620)
- Trevor van Eeuwen (ORCID: https://orcid.org/0000-0003-0549-1702)
- Yufei Xiang (ORCID: https://orcid.org/0000-0002-6732-5649)
- Scott B. Ficarro (ORCID: https://orcid.org/0000-0002-1521-7996)
- Karen Y. Linde-Garelli (ORCID: https://orcid.org/0000-0003-3438-6477)
- Kera Xibinaku (ORCID: https://orcid.org/0009-0000-1601-5555)
- Maximiliaan Hennink (ORCID: https://orcid.org/0009-0000-1589-1780)
- Maggie Chen (ORCID: https://orcid.org/0000-0002-1900-1017)
- Kimie Kondo (ORCID: https://orcid.org/0009-0002-3270-278X)
- Daniel C. Freund (ORCID: https://orcid.org/0009-0005-6950-5343)
- Kaay Matas (ORCID: https://orcid.org/0009-0004-8968-0280)
Institutions
- QB3 (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Johns Hopkins University (US)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Brown University (US)
- Johns Hopkins Medicine (US)
- The Ohio State University Wexner Medical Center (US)
- Massachusetts General Hospital (US)
- Institute of Organic Chemistry (PL)
- Dana-Farber Cancer Institute (US)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Whitehead Institute for Biomedical Research (US)
- Rockefeller University (US)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1126/science.adv7111
- Citations
- 3
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42