Related Experiment Video

Updated: May 27, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade

Xiaojun Zha1, Zhongdong Hu, Shaozong He

  • 1State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. zhaxiaojunpumc@gmail.com

Cancer Letters
|November 8, 2011
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) promotes phosphatase and tensin homolog (PTEN) transcription, inhibiting proliferation in cells with TSC1/TSC2 loss. This pathway offers protection against mTORC1-driven tumorigenesis.

Area of Science:

  • Cellular signaling pathways
  • Tumorigenesis mechanisms
  • Molecular biology

Background:

  • Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, often due to TSC1/TSC2 inactivation, inhibits Akt signaling.
  • The precise molecular mechanisms underlying this negative feedback loop are not fully elucidated.
  • Signal transducer and activator of transcription 3 (STAT3) is a known regulator of mTORC1.

Purpose of the Study:

  • To investigate the role of STAT3 in the negative feedback inhibition of Akt signaling caused by TSC1/TSC2 loss.
  • To elucidate the molecular mechanisms by which STAT3 influences this pathway.
  • To determine if STAT3-mediated PTEN activation serves as a protective mechanism against mTORC1-driven tumorigenesis.

Main Methods:

  • Investigated STAT3's role in TSC1/TSC2-deficient cells.
  • Utilized chromatin immunoprecipitation assays to assess STAT3 binding to the PTEN promoter.
  • Measured PTEN and Akt signaling levels in response to STAT3 modulation.
  • Assessed cell proliferation in Tsc1(-/-) or Tsc2(-/-) cells.

Main Results:

  • STAT3 directly binds to the PTEN promoter, promoting PTEN transcription.
  • Elevated PTEN levels down-regulate Akt signaling.
  • STAT3-mediated PTEN activation inhibits the proliferation of Tsc1(-/-) or Tsc2(-/-) cells.
  • This pathway acts as a negative feedback mechanism against hyper-activated mTORC1.

Conclusions:

  • STAT3 plays a crucial role in the negative feedback regulation of Akt signaling in response to TSC1/TSC2 loss.
  • STAT3-induced PTEN transcription is a key component of this feedback loop.
  • Activation of PTEN via STAT3 may represent a protective mechanism against mTORC1-driven tumorigenesis, contributing to the generally benign nature of TSC1/TSC2-deficient tumors.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...