Related Experiment Video

Updated: Jun 5, 2026

Development and Application of Rapamycin-regulated Tyrosine Phosphatases
06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

mTOR-dependent regulation of PHLPP expression controls the rapamycin sensitivity in cancer cells

Jianyu Liu1, Payton D Stevens, Tianyan Gao

  • 1Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536-0509, USA.

The Journal of Biological Chemistry
|December 24, 2010
PubMed

Insights

PHLPP phosphatases regulate Akt and tumor suppression. mTOR controls PHLPP expression, impacting cancer cell sensitivity to rapamycin, revealing a feedback loop crucial for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • PHLPP (PH domain and Leucine rich repeat Protein Phosphatase) isoforms, PHLPP1 and PHLPP2, are negative regulators of Akt signaling.
  • Previous research established a tumor suppressor role for PHLPP isoforms in colon cancer.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling PHLPP expression in cancer cells.
  • To elucidate the role of mTOR-dependent translation in PHLPP expression.
  • To determine the functional consequence of PHLPP regulation on cancer cell response to rapamycin.

Main Methods:

  • Utilized rapamycin treatment and RNA interference (RNAi) to modulate mTOR activity and PHLPP expression.
  • Investigated the effects of TSC2 knockdown and expression of a rapamycin-insensitive p70S6K mutant.
  • Examined the impact of 4E-BP1 depletion and amino acid/glucose starvation on PHLPP levels.
  • Assessed the functional role of PHLPP expression in rapamycin resistance in colon cancer cells.

Main Results:

  • mTOR-dependent protein translation controls PHLPP expression in colon and breast cancer cells.
  • Rapamycin treatment or mTOR knockdown decreased PHLPP protein levels, while TSC2 knockdown increased them.
  • Rapamycin-mediated PHLPP down-regulation was linked to p70S6K activity and blocked by 4E-BP1 depletion.
  • Inhibition of mTOR activity via nutrient starvation reduced PHLPP expression.
  • Rapamycin-induced PHLPP inhibition contributed to rapamycin resistance in colon cancer cells.

Conclusions:

  • Identified a compensatory feedback loop where mTOR activation up-regulates PHLPP, inhibiting Akt.
  • mTOR-dependent PHLPP expression is a key determinant of cancer cell sensitivity to rapamycin.
  • This regulatory pathway offers potential therapeutic targets for overcoming rapamycin resistance in cancer.

More Related Videos

A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction05:28

A Semi-Quantitative Drug Affinity Responsive Target Stability (DARTS) assay for studying Rapamycin/mTOR interaction

Published on: August 27, 2019

Related Concept Videos

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...
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...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
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...
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...