Controlling receptor downregulation by ubiquitination and deubiquitination

Related Experiment Video

Updated: Jul 4, 2026

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

Masayuki Komada1

  • 1Department of Biological Sciences, Tokyo Institute of Technology, 4259-B-16 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan. makomada@bio.titech.ac.jp

Current Drug Discovery Technologies
|June 10, 2008
PubMed

Insights

Receptor downregulation, crucial for preventing cell overgrowth and cancer, involves receptor tyrosine kinases (RTKs) being tagged with ubiquitin for lysosomal degradation. Deubiquitinating enzymes (DUBs) on endosomes also regulate this process, offering potential cancer treatment targets.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Receptor tyrosine kinases (RTKs) activate signaling pathways, and their downregulation prevents uncontrolled cell proliferation.
  • Defects in RTK downregulation are linked to various cancers.
  • RTKs are endocytosed and trafficked to lysosomes for degradation, a process critical for signal termination.

Purpose of the Study:

  • To review the roles and regulatory mechanisms of deubiquitinating enzymes (DUBs) in the endosomal sorting of ubiquitinated cargo proteins.
  • To highlight the importance of DUBs in receptor downregulation.
  • To identify potential therapeutic targets for RTK-driven cancers.

Main Methods:

  • Review of existing literature on DUBs, endosomal sorting, and RTK downregulation.
  • Analysis of the roles of specific DUBs (UBPY, AMSH, Doa4) in ubiquitinated protein trafficking.
  • Examination of the interplay between ubiquitination and deubiquitination in receptor sorting.

Main Results:

  • Ubiquitin tagging of activated RTKs signals their transport from endosomes to lysosomes.
  • Class E vacuolar protein sorting (Vps) proteins coordinate the sorting of ubiquitinated RTKs on endosomes.
  • Deubiquitinating enzymes (DUBs) like UBPY, AMSH, and Doa4 associate with endosomal Vps proteins and regulate cargo protein sorting.
  • RTK downregulation is controlled by both ubiquitination and deubiquitination processes.

Conclusions:

  • Endosomal DUBs play a critical role in regulating RTK downregulation and overall protein trafficking.
  • The interplay between ubiquitination and deubiquitination is essential for precise control of RTK signaling.
  • Targeting endosomal DUBs may offer novel therapeutic strategies for cancers characterized by RTK overexpression or activation.

More Related Videos

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model09:00

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model

Published on: April 17, 2026

Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples09:45

Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples

Published on: May 10, 2015

Related Concept Videos

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...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
Regulated Protein Degradation02:58

Regulated Protein Degradation

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...
Regulated Protein Degradation02:58

Regulated Protein Degradation

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...
Regulation of Expression at Multiple Steps01:23

Regulation of Expression at Multiple Steps

The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.