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.

Abstract

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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 →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mammalian cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
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

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	ERK activation; ERK-nonphosphorylatable TSC2 mutant
Target	ERK -> TSC2 -> mTORC1
Model	Mammalian cells; TSC2+/- tumour cells
Effect	ERK phosphorylates TSC2, splits TSC1-TSC2 and weakens its brake on mTORC1, promoting proliferation and transformation

In the Atlas

Links in the pathway map

Supports ERK / RSK (MAPK) inhibits TSC1/TSC2

Learn the biology

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

Cite this paper

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Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., & Pandolfi, P. P. (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. https://doi.org/10.1016/j.cell.2005.02.031

@article{MA2005,
  author       = {Ma, L. and Chen, Z. and Erdjument-Bromage, H. and Tempst, P. and Pandolfi, P. P.},
  title        = {{Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis}},
  journal      = {Cell},
  year         = {2005},
  doi          = {10.1016/j.cell.2005.02.031},
  note         = {PMID: 15851026},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record MA2005) [Data set]. https://mtor-atlas.org/study/MA2005/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_MA2005,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record MA2005},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/MA2005/},
  doi          = {10.5281/zenodo.22059963}
}

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