Related Experiment Video

Updated: Oct 25, 2025

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
06:56

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

Published on: September 6, 2024

526

RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity

Pau Castel1, Srisathiyanarayanan Dharmaiah2, Matthew J Sale1

  • 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.

Proceedings of the National Academy of Sciences of the United States of America
|August 12, 2021
PubMed

Insights

Sin1 is identified as a novel RAS effector, interacting with KRAS 4A independently of its role in mTORC2. This discovery reveals a new pathway for RAS-driven cancer signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • RAS proteins function as molecular switches, regulating downstream signaling pathways upon GTP binding.
  • Canonical RAS effectors are key targets in RAS-driven cancers, but many remain poorly understood.
  • Sin1 is known for its role in mTORC2 complex assembly and activity.

Purpose of the Study:

  • To biochemically and structurally characterize Sin1 as a potential RAS effector.
  • To investigate the functional independence of Sin1's RAS interaction from its mTORC2 functions.

Main Methods:

  • Biochemical assays to study protein interactions.
  • X-ray crystallography to determine the structure of the RAS-Sin1 complex.
  • Cellular and in vivo (mouse) models to assess functional consequences.

Main Results:

  • Sin1 interacts with KRAS isoform 4A via an atypical RAS-binding domain.
  • Structural analysis elucidated the molecular details of the RAS-Sin1 interaction.
  • Sin1's interaction with RAS is dispensable for mTORC2 assembly and activity.
  • Cells and mice with RAS-binding deficient Sin1 mutants exhibit normal mTORC2 function.

Conclusions:

  • Sin1 is a bona fide RAS effector, regulating signaling independently of mTORC2.
  • This finding uncovers a novel, mTORC2-independent signaling pathway regulated by RAS.
  • Sin1 represents a potential new therapeutic target in RAS-driven cancers.
Keywords:
KRASRASRBDSin1mTORC2

More Related Videos

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells08:47

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

Published on: May 1, 2020

3.2K
Global Identification of Co-Translational Interaction Networks by Selective Ribosome Profiling06:58

Global Identification of Co-Translational Interaction Networks by Selective Ribosome Profiling

Published on: October 7, 2021

2.6K

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...
4.2K
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...
4.0K
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...
9.7K
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...
6.7K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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...
2.7K
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...
6.6K