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Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis

Ma L; Chen Z; Erdjument-Bromage H; Tempst P; Pandolfi PP · 2005 · Cell · Atlas ID MA2005

What this study shows

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.

Tier D because it is mechanistic or in-vitro work (model: Mammalian cells), not a whole-organism health-outcome study; tier describes study design, not quality -- this is often exactly where causal biology gets established.

At a glance

Evidence tier	D Mechanistic / in vitro / review
Study type	5 - Mechanistic / In Vitro
Model system	Mammalian cells
Journal	Cell
Year	2005
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1016/j.cell.2005.02.031 · PMID 15851026

Extracted findings

Target	ERK -> TSC2 (Ser664) -> mTORC1
Model	Mammalian cells
Effect	ERK phosphorylates TSC2 and inactivates the TSC complex, activating mTORC1 independently of Akt

In the Atlas

Learn the biology

Want to understand the biology behind this study? → The TSC Complex — Where the Inputs Meet

Abstract

Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Read the full abstract on PubMed →

Cite this record

Barton, O. (2026). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis — evidence-graded record MA2005. In Oliver's mTOR Atlas. https://mtor-atlas.org/study/MA2005/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_MA2005,
  author       = {Barton, Oliver},
  title        = {{Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis} --- evidence-graded record MA2005},
  howpublished = {Oliver's mTOR Atlas},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/MA2005/},
  note         = {Dataset DOI: 10.5281/zenodo.22059963}
}

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