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Oncogene (2014) 33, 11131123& 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14
http://www.nature.com/onc
Web End =www.nature.com/onc
ORIGINAL ARTICLE
ATM kinase activity modulates ITCH E3-ubiquitin ligase activity
S Santini1,2, V Stagni1,2, R Giambruno3, G Fianco1,2, A Di Benedetto4, M Mottolese4, M Pellegrini5 and D Baril1,2
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 factora (TNFa), 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 identied as ITCH substrates. Importantly, ATM-decient mice show resistance to hepatocyte cell death, similarly to Itch-decient 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 deciency may contribute to the complex clinical features linked to Ataxia Telangiectasia.
Oncogene (2014) 33, 11131123; doi:http://dx.doi.org/10.1038/onc.2013.52
Web End =10.1038/onc.2013.52 ; published online 25 February 2013
Keywords: Ataxia Telangiectasia; ATM kinase; ITCH E3-ubiquitin ligase; c-FLIP-L; c-Jun; protein ubiquitination and degradation
INTRODUCTIONAtaxia Telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, radiosensitivity and increased cancer predisposition. A-T pathology arises from the loss of functional Ataxia Telangiectasia Mutated (ATM) protein kinase, a central guarantee for the genomic integrity of the cell. ATM is induced by DNA damage and its activity modulates the cellular response, mainly through the downstream phosphorylation of target proteins.1,2 Proteomic studies uncovered more than 700 ATM kinase substrates in response to DNA damage underlying the complexity of the signaling cascade initiated by this kinase.These studies identied the ubiquitin-proteasome system as a relevant target of ATM kinase.35 In response to DNA damage ATM phosphorylates and...