Related Experiment Video

Updated: Jul 28, 2026

RhoC GTPase Activation Assay
09:58

RhoC GTPase Activation Assay

Published on: August 22, 2010

12.9K

Tyrosine phosphorylation of RalGDS by c-Met receptor blocks its interaction with Ras

Richard Wong1, Larry A Feig1

  • 1Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts Medical School, Boston, MA, USA.

Biochemical and Biophysical Research Communications
|November 6, 2016
PubMed

Insights

c-Met receptors phosphorylate Ral Guanine Nucleotide Exchange Simulator (RalGDS) at Y752, blocking Ras binding. This mechanism may suppress Ral protein activation, potentially inhibiting Ras-driven tumor formation in certain cell types.

Area of Science:

  • Cellular signaling pathways
  • Oncogenesis and tumor suppression
  • Protein-protein interactions

Background:

  • Ral Guanine Nucleotide Exchange Simulator (RalGDS) activates Ral GTPases (RalA, RalB), crucial for Ras effector pathways.
  • Ras-GTP binding to RalGDS's Ras-binding domain (RBD) facilitates Ral GTPase activation.
  • Ral protein activation can either complement or oppose Ras-driven cellular functions, including oncogenesis.

Purpose of the Study:

  • To elucidate a biochemical mechanism by which c-Met receptors modulate Ras-RalGDS signaling.
  • To investigate the role of RalGDS phosphorylation in regulating Ras binding.
  • To understand how this regulation might influence Ras-mediated oncogenic potential and tumor suppression.

Main Methods:

  • Investigated the interaction between c-Met receptors and RalGDS.
  • Utilized tyrosine phosphorylation assays to identify specific phosphorylation sites on RalGDS.
  • Performed Ras-binding assays to assess the impact of RalGDS phosphorylation on Ras interaction.

Main Results:

  • Demonstrated that c-Met receptors promote tyrosine phosphorylation of RalGDS at Y752 within its Ras-binding domain (RBD).
  • Showed that Y752 phosphorylation of RalGDS inhibits the binding of Ras to RalGDS.
  • This inhibition of Ras-RalGDS interaction suggests a mechanism for suppressing Ral GTPase activation.

Conclusions:

  • c-Met receptor-mediated tyrosine phosphorylation of RalGDS at Y752 represents a novel regulatory mechanism.
  • This phosphorylation event serves to block Ras binding to RalGDS, thereby inhibiting Ral GTPase activation.
  • This pathway may be critical in contexts where Ras signaling contributes to tumor suppression rather than oncogenesis.
Keywords:
RalRalGDSRasTyrosine phosphorylationc-Met

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.4K
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

9.1K

Related Concept Videos

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...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
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...
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:
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...
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...