Siraj M. Ali
Identified raptor and rictor by mass spectrometry in the purifications that defined the two mTOR complexes
Mass-spectrometry proteomics collaborator on the founding raptor/rictor papers, working with the Memorial Sloan Kettering proteomics core · later Foundation Medicine and EQRx · now Head of Translational Medicine, Lunit
Translational Medicine, Lunit ↗
Portrait: The Pathologist Power List 2020
The 2002 and 2004 papers that identified raptor and rictor — the defining subunits of mTORC1 and mTORC2 — depended on mass-spectrometry protein identification carried out with Memorial Sloan Kettering Cancer Center's proteomics core, led by Hediye Erdjument-Bromage and Paul Tempst. Siraj Ali was part of that collaborative effort, helping identify the previously unknown proteins that co-purified with mTOR in David Sabatini's lab.
This kind of unbiased biochemical purification — pulling down a protein of interest and mass-spectrometry-sequencing everything that comes with it — was the method that physically revealed mTORC1's and mTORC2's core subunits, well before genome-scale tools existed. It remains a template for how signalling complexes are discovered.
The studies below, gathered in this Atlas, mark that contribution.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 Contributes to the mass-spectrometry identification of raptor, the defining subunit of mTORC1. |
| 2003 | M | GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR KIM2003 Discovered mLST8 (GbetaL), the third core subunit that clamps onto mTOR's kinase domain and stabilizes the complex. It fine-tunes how tightly Raptor holds mTOR in response to nutrients - a small but essential cog that later turned out to be especially critical for the mTORC2 complex. |
| 2004 | M | Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton SAR2004 Contributes to the mass-spectrometry identification of rictor, the defining subunit of mTORC2. |
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB SAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |