Related Experiment Video

Updated: Aug 20, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

10.0K

How to kill an ERKsome target: PROTACs deliver the deathblow

Malia B Potts1

  • 1Department of Oncology Research, Amgen Research, Thousand Oaks, CA 91320, USA.

Cell Chemical Biology
|November 18, 2022
PubMed

Insights

Selective degradation of ERK5 (Extracellular signal-regulated kinase 5) does not reduce proliferation or inflammation, challenging prior assumptions. This study showcases Proteolysis-targeting chimeras (PROTACs) for exploring protein functions beyond enzymatic activity.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Drug Discovery

Background:

  • Extracellular signal-regulated kinase 5 (ERK5) is implicated in cellular processes like proliferation and inflammation.
  • Previous research suggested ERK5 inactivation mediates anti-proliferative and anti-inflammatory effects.
  • A longstanding debate exists regarding the precise roles of ERK5 in these cellular responses.

Purpose of the Study:

  • To investigate the specific functions of ERK5 by selectively degrading the protein.
  • To determine if ERK5 degradation impacts cellular proliferation and inflammatory responses.
  • To assess the utility of Proteolysis-targeting chimeras (PROTACs) in dissecting non-enzymatic protein functions.

Main Methods:

  • Utilized PROTAC technology for targeted degradation of ERK5.
  • Assessed cellular proliferation rates following ERK5 degradation.
  • Measured inflammatory markers and responses in cells with degraded ERK5.

Main Results:

  • Selective degradation of ERK5 did not result in significant anti-proliferative effects.
  • ERK5 degradation did not exhibit anti-inflammatory activities.
  • The findings challenge previously attributed roles of ERK5 inactivation.

Conclusions:

  • The non-enzymatic functions previously attributed to ERK5 inactivation are not supported by selective degradation.
  • PROTACs are powerful tools for precisely investigating the biological roles of target proteins, including their non-enzymatic activities.
  • This study resolves a significant debate in the field regarding ERK5 function.

More Related Videos

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes07:22

Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes

Published on: January 12, 2024

3.6K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.3K

Related Concept Videos

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...
7.8K
Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
7.1K
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.6K
Protein Networks02:26

Protein Networks

An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.1K
Tail-anchoring of Proteins in the ER Membrane01:45

Tail-anchoring of Proteins in the ER Membrane

Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
3.1K
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
8.9K