Related Experiment Video
Updated: Jul 5, 2025
06:56
Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
Published on: September 6, 2024
391
SPOP negatively regulates mTORC1 activity by ubiquitinating Sec13
Yong Yang1, Yan-Chun Han2, Qi Cao2
1The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong 256603, China.
Cellular Signalling
|January 19, 2024
Summary
SPOP-mediated ubiquitination of Sec13, a GATOR2 component, suppresses mTORC1 signaling. This finding reveals SPOP as a tumor suppressor by inhibiting cancer cell proliferation and migration via the mTORC1 pathway.
Area of Science:
- Cellular signaling
- Molecular biology
- Cancer research
Background:
- Mammalian target of rapamycin complex1 (mTORC1) regulates metabolism and cell growth in response to amino acids.
- GATOR2 is crucial in amino acid-mediated mTORC1 signaling by inhibiting GATOR1's GTPase activity (GAP).
- The precise mechanism by which GATOR2 regulates mTORC1 signaling remains incompletely understood.
Purpose of the Study:
- To elucidate the role of GATOR2 components in mTORC1 pathway regulation.
- To investigate the mechanism of GATOR2-mediated suppression of mTORC1 activity.
- To determine the function of SPOP in breast cancer cell proliferation and migration.
Main Methods:
- Investigated K63-ubiquitination of Sec13, a GATOR2 component.
- Utilized SPOP-mediated ubiquitination assays.
- Assessed the impact of SPOP and Sec13 on mTORC1 activity.
- Examined breast cancer cell proliferation and migration in vitro.
Main Results:
- K63-ubiquitination of Sec13 by SPOP suppresses mTORC1 activity by reducing GATOR2 complex interactions.
- Ubiquitination of Sec13 by SPOP attenuates its interaction with other GATOR2 components, inhibiting mTORC1.
- SPOP deficiency enhances breast cancer cell proliferation and migration, effects reversed by Sec13 knockdown.
Conclusions:
- SPOP acts as a tumor suppressor by negatively regulating the mTORC1 signaling pathway through Sec13 ubiquitination.
- The SPOP-Sec13-GATOR2 axis represents a novel regulatory mechanism in mTORC1 signaling.
- Targeting the SPOP-mediated pathway could offer therapeutic strategies for breast cancer.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
3.6K
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...
3.6K
03:03mTOR Signaling and Cancer Progression
3.8K
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 mTOR pathway or the...
3.8K
01:20The JAK-STAT Signaling Pathway
8.9K
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...
8.9K
02:58Regulated Protein Degradation
7.3K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.3K
02:19The Spindle Assembly Checkpoint
3.2K
The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
3.2K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K