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Related Concept Videos

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.
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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.
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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.
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Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples
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ERBB2 is a target for USP8-mediated deubiquitination.

Inez M J Meijer1, Jeroen E M van Leeuwen

  • 1Department of Cell & Applied Biology, Faculty of Science, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Cellular Signalling
|November 4, 2010
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The study reveals that Usp8 deubiquitinase is involved in the endosomal trafficking of the ErbB2 receptor. This finding clarifies the regulation of ErbB2 signaling pathways in cancer.

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Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • ErbB receptor tyrosine kinases, including EGFR and ErbB2, are crucial in cell signaling and implicated in tumorigenesis when dysregulated.
  • EGFR signaling attenuation involves endocytosis and ubiquitination by the E3-ligase Cbl, followed by deubiquitination by Usp8 en route to lysosomes.
  • ErbB2 exhibits enhanced recycling, leading to the hypothesis that Usp8 might not be involved in its trafficking pathway.

Purpose of the Study:

  • To investigate the role of Usp8 in the endosomal trafficking pathway of the ErbB2 receptor.
  • To elucidate the mechanisms of Usp8 interaction with EGFR-ErbB2 chimeric receptors.

Main Methods:

  • Utilized a chimeric EGFR-ErbB2 receptor system to study receptor trafficking and ubiquitination.
  • Employed techniques to assess EGF-induced polyubiquitination, tyrosine phosphorylation of Cbl and Usp8, and the impact of Usp8 mutants on EGFR-ErbB2 ubiquitination.

Main Results:

  • EGF stimulation induced K63-polyubiquitination of the EGFR-ErbB2 chimeric receptor, dependent on the Cbl binding site.
  • EGF stimulation also led to tyrosine phosphorylation of Usp8, which was dependent on Src and EGFR-ErbB2 kinase activity.
  • Coexpression of catalytically inactive Usp8 enhanced EGFR-ErbB2 ubiquitination, indicating Usp8's role in deubiquitination within the ErbB2 pathway.

Conclusions:

  • Usp8 is demonstrated to be part of the ErbB2 endosomal trafficking pathway.
  • Usp8 deubiquitinates EGFR-ErbB2, influencing its trafficking and signaling.
  • These findings contribute to understanding the regulation of ErbB receptor signaling in cancer.