ERK / RSK (MAPK)
The Ras-MAPK growth-signalling arm. ERK and its effector RSK phosphorylate TSC2 and inactivate the TSC complex, so MAPK signalling converges on the same brake that Akt releases (MA2005). This is the third major upstream input to mTORC1 alongside PI3K/Akt and AMPK, and it is a route to mTORC1 activation that PI3K inhibitors do not close. mTORC1 inhibition also feeds back to activate MAPK (CAR2008).
A second growth pathway that presses the same brake. A separate growth-signaling chain that reaches mTORC1 through its own route. Two of its members disable the TSC brake, the same brake that Akt also releases - so this is a third major way to switch mTORC1 on, one that drugs blocking PI3K don't touch. mTORC1 can also feed back and switch this chain on.
ERK S664 and RSK S1798 on TSC2. mTORC1 inhibition relieves feedback and activates MAPK PI3K-dependently – the basis for combined mTOR/MEK strategies.
TL;DR. ERK / RSK (MAPK) appears in 4 curated studies in Oliver's mTOR Atlas: 4 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 3 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| ERK / RSK (MAPK) inhibits TSC1/TSC2 mechanism: phosphorylation · this link in full · on the map table | A separate growth pathway also disables the TSC brake – a third route into mTORC1 that drugs blocking only PI3K/Akt can't shut down. ERK phosphorylates TSC2 and inactivates the TSC complex, so Ras-MAPK growth signalling converges on the same brake that Akt releases. This is the third upstream arm alongside PI3K/Akt and AMPK, and clinically it is a route to mTORC1 activation that PI3K inhibitors do not close. ERK phosphorylates TSC2 and inactivates the TSC complex, so Ras-MAPK growth signalling converges on the same brake that Akt releases. This is the third upstream arm alongside PI3K/Akt and AMPK, and clinically it is a route to mTORC1 activation that PI3K inhibitors do not close. Holds under: Single-study edge in this corpus; Roux 2004 describes the parallel RSK arm and is not yet held. plausible in people, not shown directly · emerging, few independent studies | M | MA2005 |
| ERK / RSK (MAPK) activates Nucleotide synthesis mechanism: phosphorylation · this link in full · on the map table | ERK2 switches on an enzyme that makes purines. ERK2 directly phosphorylates the purine-making enzyme PFAS within minutes, speeding de novo purine synthesis. This growth signal for DNA and RNA building blocks runs in parallel to mTORC1's own routes. ERK2 directly phosphorylates the purine-making enzyme PFAS within minutes, speeding de novo purine synthesis. This growth signal for DNA and RNA building blocks runs in parallel to mTORC1's own routes. Holds under: Human cancer cell lines and xenograft tumours; ERK2, not ERK1; post-translational and parallel to mTORC1. Single study. plausible in people, not shown directly · emerging, few independent studies | M | ALI2020 |
| mTORC1 inhibits ERK / RSK (MAPK) mechanism: signal-relay · this link in full · on the map table | Blocking mTORC1 can backfire by releasing a brake on a different growth pathway (MAPK) – one reason mTOR-blocking drugs alone often aren't enough. A second feedback arm: inhibiting mTORC1 releases a PI3K-dependent brake and MAPK signalling goes up. Together with S6K1-IRS1 this is why single-agent mTOR inhibition tends to be met by compensatory growth signalling. A second feedback arm: inhibiting mTORC1 releases a PI3K-dependent brake and MAPK signalling goes up. Together with S6K1-IRS1 this is why single-agent mTOR inhibition tends to be met by compensatory growth signalling. Holds under: Single-study edge in this corpus. CAR2008 includes tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), in which MAPK activation depended on the dosing schedule, plus a mouse prostate cancer model, xenografts and cell lines. shown in people · settled in the literature | M | CAR2008 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 4 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | M | Phosphorylation of OTUB1 promotes autophagy initiation under starvation SUN2026B Under starvation, ERK phosphorylates the deubiquitinase OTUB1 at S118, which stabilizes it by letting it out-compete TRIM29 for binding to ANXA2. Stabilized OTUB1 upregulates DEPTOR, a natural mTOR inhibitor, which suppresses mTOR and triggers autophagy. In mice, restoring this fasting-triggered ERK-OTUB1-DEPTOR-mTOR axis countered the mTOR-activating effect of a Western diet and eased MASLD (fatty liver disease) progression, giving a mechanistic account of how fasting benefits the liver. |
| 2020 | M | ERK2 phosphorylates PFAS to mediate posttranslational control of de novo purine synthesis ALI2020 The Atlas records several routes by which mTORC1 drives purine synthesis. This study shows mTORC1 is not the only growth pathway with that power: RAS-ERK signalling stimulates purine synthesis directly and within minutes, because ERK2 - but not ERK1 - phosphorylates the purine synthesis enzyme PFAS at Thr619. Cells expressing a PFAS that cannot be phosphorylated make fewer purines, form fewer colonies and grow smaller tumors. Two points bound the mTOR claim: the control is posttranslational, so it acts far faster than transcription or translation, and it is a parallel input, so purine synthesis in a RAS-driven tumor is not read out from mTORC1 activity alone. |
| 2008 | M | Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer CAR2008 mTORC1 inhibition activates the MAPK pathway via a PI3K-dependent feedback loop. Seen in tumour biopsies from patients with advanced solid tumours treated with RAD001 (everolimus), where the rise depended on the dosing schedule, and in a mouse prostate cancer model, xenografts and cell lines. |
| 2005 | M | Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis MA2005 The MAPK input to mTORC1. In mammalian cells, ERK phosphorylates TSC2 and inactivates the TSC complex, so growth signalling through Ras/ERK converges on the same brake that Akt releases. This is the third major upstream arm alongside PI3K/Akt and AMPK. Its practical significance is that it offers a route to mTORC1 activation that PI3K inhibitors do not close - though that inference is mechanistic; no human data here. |
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