Related Experiment Video

Updated: Jun 25, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

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

Published on: May 20, 2020

ErbB2 and ErbB4 Cbl binding sites can functionally replace the ErbB1 Cbl binding site

Suzanne M Jansen1, Laura S Sleumer, Ester Damen

  • 1Department of Cell Biology, Faculty of Science, Radboud University Nijmegen, Heijendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.

Cellular Signalling
|March 6, 2009
PubMed

Insights

Poor downregulation of ErbB2 and ErbB4 receptors is not caused by variations in their Cbl binding sites. This finding challenges previous hypotheses linking Cbl E3 ligase recruitment to ErbB receptor downregulation and tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Poor downregulation of ErbB receptors, particularly ErbB-2, -3, and -4 compared to ErbB1, is linked to increased downstream signaling and cancer development.
  • Previous research suggested that reduced Cbl E3 ligase protein recruitment contributes to the impaired downregulation of ErbB-2, -3, and -4 receptors.

Purpose of the Study:

  • To investigate whether sequence variations in the Cbl binding site of ErbB2 and ErbB4 receptors contribute to their poor downregulation compared to ErbB1/EGFR.
  • To determine if replacing the ErbB1 Cbl binding site with those from ErbB2 or ErbB4 affects Cbl recruitment, ubiquitination, and degradation.

Main Methods:

  • Utilized retroviral infection to introduce modified EGFR constructs into NIH3T3 cells.
  • Replaced the native Cbl binding site in EGFR (ErbB1) with the corresponding sequences from ErbB2 and ErbB4.
  • Assessed Cbl recruitment, receptor ubiquitination, receptor degradation, and ligand degradation following receptor stimulation.

Main Results:

  • A mutation in the EGFR Cbl binding site (Y1045F) significantly impaired Cbl recruitment, EGFR ubiquitination, and delayed EGFR degradation, confirming the site's importance.
  • Replacing the EGFR Cbl binding site with sequences from ErbB2 or ErbB4 did not alter Cbl recruitment, receptor ubiquitination, or receptor degradation.
  • Downstream signaling and ligand degradation remained unaffected by the Cbl binding site modifications in EGFR.

Conclusions:

  • The sequence variations within the Cbl binding site of ErbB2 and ErbB4 receptors are not the cause of their poor downregulation.
  • The findings suggest that other mechanisms, beyond Cbl binding site differences, are responsible for the differential downregulation of ErbB receptors.
  • This research refutes a key hypothesis regarding the role of Cbl E3 ligase recruitment in ErbB receptor downregulation and tumorigenesis.

More Related Videos

Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification (BiCAP)06:45

Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification (BiCAP)

Published on: June 15, 2018

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...