Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

Marcotullio, Lucia Di; Greco, Azzura; Mazzà, Daniela; Canettieri, Gianluca; Pietrosanti, Laura; Infante, Paola; Coni, Sonia; Moretti, Marta; Smaele, Enrico De; Ferretti, Elisabetta; Screpanti, Isabella; Gulino, Alberto

doi:10.1038/onc.2010.394

Cited by 101 publications

(113 citation statements)

References 55 publications

(72 reference statements)

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“…Whether YAP relocates between p73/YAP targets and TEAD/YAP targets in response to ITCH is to be determined in future studies. Although ITCH is emerging as a prosurvival factor, ITCH may also catalyze degradation of prooncogeneic factors, such as the Gli transcription factor that is deregulated in medulloblastomas (46). Further investigation of ITCH phenotypes in animal models is required to uncover its role in tumorogenesis and in different contexts.…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity

2011

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The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domaincontaining proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein-protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis. Cancer Res; 71(5);

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Section: Discussionmentioning

confidence: 99%

Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity

2011

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“…In fact, our results show that ITCH knockdown or genetic KO is associated with reduced WWOX ubiquitination and stabilization and thus, impaired DDR. ITCH ubiquitinates and regulates the stability of several substrates, including p73 (50), p63 (51), Gli (52), and others (53); therefore, we cannot exclude that other proteins could also contribute to its observed role in DDR. Although ITCH has been shown to function as a prosurvival factor (54), our results suggest that it can also contribute to other functions important for the neoplastic process.…”

Section: Discussionmentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

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Genomic instability is a hallmark of cancer. The WW domaincontaining oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.genomic instability | common fragile sites | WW domain-containing oxidoreductase | ataxia telangiectasia-mutated | ITCH G enomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1-3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10-13). Ectopic expression of WWOX in WWOXnegative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10,11,14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14-16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19,20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22-24). ...

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“…39 ITCH is a member of the HECT (homologous to E6-associated protein C terminus) family of E3 ubiquitin ligases and drives turnover of a number of transcription factors. 39,42 Our data suggest that IKKb is an essential component of the ITCH and GLI1 multiprotein ubiquitin-conjugating complex, and IKKb-mediated phosphorylation of GLI1 within its C-terminal region is a regulatory step that inhibits GLI1 ubiquitination and degradation. We propose that phosphorylation of GLI1 by IKKb sets in motion a sequence of events restricting the binding of GLI1 to ITCH, resulting in decreased ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 99%

“…39 We hypothesized that IKKb-mediated phosphorylation of GLI1 may inhibit ITCH-mediated GLI1 ubiquitination, contributing to GLI1 protein stabilization. To address this possibility, we individually examined the phosphorylation status of GLI1 after deleting a cluster of 6 serine amino acid residues (S543-S548; DGLI1) or replacing serine 1071 (S1071A) or threonine 1074 (T1074A) with alanine from the full-length GLI1 construct using anti-GLI1 antibody (that recognizes phosphorylated GLI1 protein).…”

Section: Characterization Of the Ikkb-mediated Gli1 Phosphorylation Smentioning

confidence: 99%

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Agarwal¹,

Kim²,

Kunkalla³

et al. 2016

Blood

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• IKKb, independently of NF-kB, regulates the stability and transcriptional activity of GLI1 oncogene.• Combined inhibition of IKKb and GLI1 activities synergistically decreases DLBCL cell viability in vivo and in vitro.GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-a (TNFa) mediated IKKb activation-impaired GLI1 binding with the E3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL. (Blood. 2016;127(5):605-615)

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Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal

Cited by 101 publications

References 55 publications

Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity

Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

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