title: ATM kinase activity modulates ITCH E3-ubiquitin ligase activity.
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.
authors: 1] 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.
authors: S
authors: S
authors: Santini
authors: 1] 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.
authors: V
authors: V
authors: Stagni
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: R
authors: R
authors: Giambruno
authors: 1] 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.
authors: G
authors: G
authors: Fianco
authors: Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
authors: A
authors: A
authors: Di Benedetto
authors: Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
authors: M
authors: M
authors: Mottolese
authors: Department of Experimental Medicine, University of Rome 'La Sapienza', Rome, Italy.
authors: M
authors: M
authors: Pellegrini
authors: 1] 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.
authors: D
authors: D
authors: Barilà
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins