ATM kinase activity modulates ITCH E3-ubiquitin ligase activity

S. Santini, V. Stagni, R. Giambruno, G. Fianco, A. Di Benedetto, M. Mottolese, M. Pellegrini, D. Barilà

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 languageEnglish
Pages (from-to)1113-1123
Number of pages11
JournalOncogene
Volume33
Issue number9
DOIs
Publication statusPublished - Feb 27 2014

Fingerprint

Ataxia Telangiectasia
Ubiquitin-Protein Ligases
Phosphotransferases
Ubiquitination
DNA Damage
CASP8 and FADD-Like Apoptosis Regulating Protein
Th2 Cells
Hedgehogs
Proteasome Endopeptidase Complex
Hepatocytes
Cell Death
Tumor Necrosis Factor-alpha
Lymphocytes

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 journalArticle

Santini, S, Stagni, V, Giambruno, R, Fianco, G, Di Benedetto, A, Mottolese, M, Pellegrini, M & Barilà, D 2014, 'ATM kinase activity modulates ITCH E3-ubiquitin ligase activity', Oncogene, vol. 33, no. 9, pp. 1113-1123. https://doi.org/10.1038/onc.2013.52
Santini S, Stagni V, Giambruno R, Fianco G, Di Benedetto A, Mottolese M et al. ATM kinase activity modulates ITCH E3-ubiquitin ligase activity. Oncogene. 2014 Feb 27;33(9):1113-1123. https://doi.org/10.1038/onc.2013.52
Santini, S. ; Stagni, V. ; Giambruno, R. ; Fianco, G. ; Di Benedetto, A. ; Mottolese, M. ; Pellegrini, M. ; Barilà, D. / ATM kinase activity modulates ITCH E3-ubiquitin ligase activity. In: Oncogene. 2014 ; Vol. 33, No. 9. pp. 1113-1123.
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