Related Experiment Video

Updated: Mar 26, 2026

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.7K

The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity

Feike Hao1,2, Takashi Itoh1, Eiji Morita3

  • 1Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Japan.

FEBS Letters
|January 21, 2016
PubMed

Insights

Myotubularin-related protein 3 (MTMR3) interacts with mTORC1, a key regulator of cell growth and autophagy. Overexpression of MTMR3, especially phosphatase-deficient forms, inhibits mTORC1, suggesting a novel PI3P-associated regulatory pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Macroautophagy is a critical cellular process for degrading intracellular components.
  • Myotubularin-related protein 3 (MTMR3), a phosphatidylinositol (PI) 3-phosphatase, has been previously linked to autophagy induction upon overexpression.
  • The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and autophagy.

Purpose of the Study:

  • To investigate the interaction between MTMR3 and mTORC1.
  • To elucidate the role of MTMR3 in regulating mTORC1 activity.
  • To identify the domains of MTMR3 responsible for mTORC1 regulation.

Main Methods:

  • Co-immunoprecipitation assays to detect MTMR3-mTORC1 interaction.
  • Western blotting to assess mTORC1 activity.
  • Site-directed mutagenesis to generate phosphatase-deficient MTMR3 variants.
  • Confocal microscopy for protein localization studies.

Main Results:

  • MTMR3 was found to interact with mTORC1.
  • Overexpression of MTMR3 inhibited mTORC1 activity, with phosphatase-deficient variants showing stronger inhibition.
  • The N-terminal half of MTMR3, containing PH-G and phosphatase domains, was sufficient for mTORC1 inhibition.
  • Phosphatase-deficient MTMR3 localized to the Golgi apparatus.

Conclusions:

  • MTMR3 directly interacts with and inhibits mTORC1 activity.
  • Phosphatase activity of MTMR3 is not essential, and may even hinder, its ability to suppress mTORC1.
  • These findings reveal a novel regulatory mechanism of mTORC1 involving MTMR3 and its association with PI3P at the Golgi.
Keywords:
MTMR3PI3PPtdlns3P phosphataseautophagymTORmTOR complex1

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

17.9K
Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases06:56

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

Published on: September 6, 2024

859

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...
6.3K
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...
5.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.7K
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...
13.8K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
20.6K
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...
9.2K