Related Experiment Video

Updated: Jul 8, 2026

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

Integration of transforming growth factor beta and RAS signaling silences a RAB5 guanine nucleotide exchange factor

Hailiang Hu1, Marc Milstein, Joanne M Bliss

  • 1Department of Biological Chemistry, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Molecular and Cellular Biology
|December 28, 2007
PubMed

Insights

Transforming growth factor beta (TGF-beta) receptor signaling is regulated by RIN1. Persistent RAS signaling silences RIN1, impacting receptor tyrosine kinase (RTK) stability and promoting breast cancer cell motility.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGF-beta) receptor (TbetaR) signaling plays a dual role in development and cancer.
  • Receptor tyrosine kinases (RTKs) are critical regulators of cell signaling, often dysregulated in cancer.

Purpose of the Study:

  • To investigate the role of RIN1, a RAB5 guanine nucleotide exchange factor (GEF), in TGF-beta receptor signaling.
  • To elucidate the mechanism by which RIN1 influences TbetaR trafficking and RTK stability.
  • To understand how RAS signaling integrates with TGF-beta signaling through RIN1 in cancer.

Main Methods:

  • Investigated the interaction between RIN1, TbetaR, and SNAI1.
  • Analyzed the effect of TGF-beta and RAS signaling on RIN1 expression and RTK stability.
  • Examined the impact of RIN1 silencing on breast cancer cell behavior, including motility and growth factor sensitivity.

Main Results:

  • RIN1 promotes TbetaR signaling via enhanced endocytosis.
  • TbetaR activation induces SNAI1, which represses RIN1 expression, creating a negative feedback loop.
  • Persistent RAS signaling stabilizes SNAI1, leading to RIN1 silencing and RTK stabilization.
  • RIN1 silencing in breast cancer cells increased sensitivity to hepatocyte growth factor and enhanced cell motility.

Conclusions:

  • TGF-beta and RAS signaling pathways are integrated through RIN1 silencing in certain tumor cells.
  • RIN1 silencing reduces RAB5-mediated endocytosis, altering cell signaling and promoting cancer progression.
  • These findings reveal mechanisms for differential TGF-beta signaling interpretation in normal versus cancer cells.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

RhoC GTPase Activation Assay09:58

RhoC GTPase Activation Assay

Published on: August 22, 2010

Related Concept Videos

Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Cell Polarization by Rho Proteins01:21

Cell Polarization by Rho Proteins

Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42,...
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...
Rab Proteins01:14

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...