Related Experiment Video

Updated: Jun 15, 2026

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
08:47

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR

Lijun Yan1, Virginie Mieulet, Darren Burgess

  • 1Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, AB T6G IZ2, Canada.

Molecular Cell
|March 16, 2010
PubMed

Insights

Amino acid levels regulate the mTORC1 pathway via the kinase MAP4K3. Phosphorylation of MAP4K3 at Ser170 activates mTORC1, while dephosphorylation by PP2A inhibits it during nutrient scarcity.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) pathway is crucial for cell growth and is activated by nutrients like glucose and amino acids.
  • The Ste20 family kinase MAP4K3 acts upstream of mTORC1 and is known to be regulated by amino acid availability.

Purpose of the Study:

  • To elucidate the regulatory mechanism of MAP4K3 activity in response to amino acid sufficiency.
  • To identify the specific molecular events governing MAP4K3's role in mTORC1 signaling under varying nutrient conditions.

Main Methods:

  • Investigated MAP4K3 activity and its regulation by amino acid levels.
  • Identified and characterized a key phosphorylation site (Ser170) in MAP4K3.
  • Utilized techniques to study the interaction between MAP4K3, protein phosphatase 2A (PP2A), and the PR61 epsilon subunit.

Main Results:

  • A transautophosphorylation site, Ser170, in MAP4K3 was identified as essential for its activity and subsequent mTORC1 activation.
  • Amino acid withdrawal leads to Ser170 dephosphorylation mediated by PP2A complexed with PR61 epsilon.
  • Inhibiting PR61 epsilon expression blocked Ser170 dephosphorylation and impaired mTORC1 inhibition during amino acid deprivation.

Conclusions:

  • Phosphorylated MAP4K3 at Ser170 activates mTORC1 signaling during amino acid sufficiency.
  • Upon amino acid restriction, MAP4K3 interacts with PP2A(T61 epsilon), leading to Ser170 dephosphorylation and inhibition of both MAP4K3 and mTORC1 signaling.

More Related Videos

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

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...
Microtubule Associated Proteins (MAPs)01:42

Microtubule Associated Proteins (MAPs)

Microtubule function and architecture are regulated by an array of specialized proteins called microtubule-associated proteins or MAPs. These proteins are widespread across different organisms and have conserved protein motifs, like the multi-TOG domain for tubulin binding found in the CLASP family of MAPs. Some MAPs are lineage-specific based on their conserved domains. Their functions depend upon the cytoskeletal architecture and cell type they are located within. In-plant cells, a specific...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...