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Updated: May 13, 2026
06:06
In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
ATM kinase activity modulates ITCH E3-ubiquitin ligase activity
S Santini1, V Stagni1, R Giambruno2
11] Department of Biology, University of Rome 'Tor Vergata', Rome, Italy [2] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, Rome, Italy.
Oncogene
|February 26, 2013
Summary
Ataxia Telangiectasia Mutated (ATM) kinase activates the ITCH E3-ubiquitin ligase, enhancing DNA damage response pathways. This ATM-ITCH interaction impacts cellular signaling and may explain Ataxia Telangiectasia symptoms.
Area of Science:
- Molecular Biology
- Cellular Signaling
- DNA Damage Response
Background:
- Ataxia Telangiectasia Mutated (ATM) kinase is crucial for DNA damage response.
- ATM regulates E3-ubiquitin ligases, impacting the ubiquitination-proteasome system.
- ITCH, an E3-ubiquitin ligase, regulates diverse cellular processes including DNA damage response.
Purpose of the Study:
- To identify novel regulators of ITCH E3-ubiquitin ligase activity.
- To elucidate the role of ATM in modulating ITCH function.
- To investigate the in vivo relevance of the ATM-ITCH interaction in cellular protection.
Main Methods:
- Biochemical assays to assess E3-ubiquitin ligase activity.
- Site-directed mutagenesis to identify key residues in ITCH activation.
- Analysis of ATM-deficient and Itch-deficient mouse models.
Main Results:
- ATM positively modulates ITCH E3-ubiquitin ligase activity via phosphorylation of S161 residue.
- Activated ITCH promotes ubiquitination and degradation of c-FLIP-L and c-Jun.
- ATM-deficient mice exhibit resistance to hepatocyte cell death, similar to Itch-deficient mice.
Conclusions:
- ITCH is a novel component of the ATM-dependent signaling pathway.
- ATM-dependent regulation of ITCH influences cellular protection mechanisms.
- Dysfunctional ITCH due to ATM deficiency may contribute to Ataxia Telangiectasia pathogenesis.
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