Abstract
Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factorα (TNFα), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM-dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia.
| Original language | English |
|---|---|
| Pages (from-to) | 1113-1123 |
| Number of pages | 11 |
| Journal | Oncogene |
| Volume | 33 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Feb 27 2014 |
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Keywords
- Ataxia Telangiectasia
- ATM kinase
- c-FLIP-L
- c-Jun
- ITCH E3-ubiquitin ligase
- protein ubiquitination and degradation
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
ATM kinase activity modulates ITCH E3-ubiquitin ligase activity. / Santini, S.; Stagni, V.; Giambruno, R.; Fianco, G.; Di Benedetto, A.; Mottolese, M.; Pellegrini, M.; Barilà, D.
In: Oncogene, Vol. 33, No. 9, 27.02.2014, p. 1113-1123.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ATM kinase activity modulates ITCH E3-ubiquitin ligase activity
AU - Santini, S.
AU - Stagni, V.
AU - Giambruno, R.
AU - Fianco, G.
AU - Di Benedetto, A.
AU - Mottolese, M.
AU - Pellegrini, M.
AU - Barilà, D.
PY - 2014/2/27
Y1 - 2014/2/27
N2 - Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factorα (TNFα), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM-dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia.
AB - Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factorα (TNFα), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM-dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia.
KW - Ataxia Telangiectasia
KW - ATM kinase
KW - c-FLIP-L
KW - c-Jun
KW - ITCH E3-ubiquitin ligase
KW - protein ubiquitination and degradation
UR - http://www.scopus.com/inward/record.url?scp=84896702019&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896702019&partnerID=8YFLogxK
U2 - 10.1038/onc.2013.52
DO - 10.1038/onc.2013.52
M3 - Article
C2 - 23435430
AN - SCOPUS:84896702019
VL - 33
SP - 1113
EP - 1123
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 9
ER -