Pier Paolo Pandolfi
Discovered that ERK directly phosphorylates and inactivates TSC2, wiring Ras/MAPK signaling into mTORC1 control
MD (1989) and PhD (1995), University of Perugia · postgraduate research, Royal Postgraduate Medical School, London (Arthur Zelent lab) · faculty, Memorial Sloan-Kettering Cancer Center & Weill Cornell Medical College (1994–2007) · Director of Cancer Genetics, then Cancer Research Institute, Beth Israel Deaconess Medical Center / Harvard Medical School (2007–2019) · now Scientific Director, William N. Pennington Cancer Institute, Renown Health, with Desert Research Institute, Reno NV (since 2020)
Professional profile, William N. Pennington Cancer Institute, Renown Health / DRI ↗
Akt is the textbook route that inactivates the TSC1–TSC2 brake on mTORC1, but it isn't the only one. In 2005, Pandolfi's group showed that ERK — the kinase at the business end of the Ras/MAPK growth pathway — directly phosphorylates TSC2 at sites distinct from Akt's, and that this is enough to functionally inactivate the TSC complex on its own. That gives mTORC1 a second, independent input arm alongside PI3K/Akt and AMPK. His group extended this logic clinically in 2008, showing that inhibiting mTORC1 with rapalogs in cancer cells paradoxically activates MAPK/ERK signaling through a PI3K-dependent feedback loop — one of the key mechanistic reasons single-node mTOR inhibitors often disappoint as cancer monotherapies.
Pandolfi's research career began as an MD/PhD student in Perugia studying acute promyelocytic leukemia (APL), then continued as a postdoctoral researcher in London, where his transgenic-mouse work helped explain why PML-RARA-driven APL responds to retinoic acid while PLZF-RARA-driven APL does not. At Memorial Sloan-Kettering and Weill Cornell (1994–2007) his lab built the Pten knockout mouse, establishing PTEN as a haploinsufficient tumor suppressor. At Beth Israel Deaconess / Harvard Medical School (2007–2019) his group proposed the competing endogenous RNA (ceRNA) hypothesis — that a pseudogene's mRNA can act as a molecular 'sponge' for microRNAs and thereby regulate a protein-coding gene like PTEN.
Since 2020 Pandolfi has directed cancer research at the William N. Pennington Cancer Institute, Renown Health, jointly with the Desert Research Institute, in Reno, Nevada. He continues to publish on APL, PTEN/PI3K–mTOR signaling, and cancer genetics.
Milestones in the Atlas
| Year | Evidence | Study |
|---|---|---|
| 2005 | M | Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis MA2005 Shows that ERK directly phosphorylates and inactivates TSC2, giving Ras/MAPK signaling a route into mTORC1 activation that runs independently of PI3K/Akt. |
| 2008 | M | Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer CAR2008 Shows that inhibiting mTORC1 in human cancer cells activates MAPK pathway signaling through a PI3K-dependent feedback loop. |