{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T05:21:26Z","timestamp":1771737686949,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"a personal private grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>EphB4 angiogenic kinase over-expression in Mesothelioma cells relies upon a degradation rescue signal provided by autocrine IGF-II activation of Insulin Receptor A. However, the identity of the molecular machinery involved in EphB4 rapid degradation upon IGF-II signal deprivation are unknown. Using targeted proteomics, protein\u2013protein interaction methods, PCR cloning, and 3D modeling approaches, we identified a novel ubiquitin E3 ligase complex recruited by the EphB4 C tail upon autocrine IGF-II signal deprivation. We show this complex to contain a previously unknown N-Terminal isoform of Deltex3 E3-Ub ligase (referred as \u201cDTX3c\u201d), along with UBA1(E1) and UBE2N(E2) ubiquitin ligases and the ATPase\/unfoldase Cdc48\/p97. Upon autocrine IGF-II neutralization in cultured MSTO211H (a Malignant Mesothelioma cell line that is highly responsive to the EphB4 degradation rescue IGF-II signal), the inter-molecular interactions between these factors were enhanced and their association with the EphB4 C-tail increased consistently with the previously described EphB4 degradation pattern. The ATPase\/unfoldase activity of Cdc48\/p97 was required for EphB4 recruitment. As compared to the previously known isoforms DTX3a and DTX3b, a 3D modeling analysis of the DTX3c Nt domain showed a unique 3D folding supporting isoform-specific biological function(s). We shed light on the molecular machinery associated with autocrine IGF-II regulation of oncogenic EphB4 kinase expression in a previously characterized IGF-II+\/EphB4+ Mesothelioma cell line. The study provides early evidence for DTX3 Ub-E3 ligase involvement beyond the Notch signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms24087380","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T05:51:41Z","timestamp":1681710701000},"page":"7380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel Isoform DTX3c Associates with UBE2N-UBA1 and Cdc48\/p97 as Part of the EphB4 Degradation Complex Regulated by the Autocrine IGF-II\/IRA Signal in Malignant Mesothelioma"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5911-1640","authenticated-orcid":false,"given":"Pierluigi","family":"Scalia","sequence":"first","affiliation":[{"name":"The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA and 93100 Caltanissetta, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Merali","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility, Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Barrero","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility, Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Suma","sequence":"additional","affiliation":[{"name":"Institute of Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Carnevale","sequence":"additional","affiliation":[{"name":"Institute of Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salim","family":"Merali","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility, Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Williams","sequence":"additional","affiliation":[{"name":"The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA and 93100 Caltanissetta, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.molcel.2018.04.006","article-title":"C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases","volume":"70","author":"Lin","year":"2018","journal-title":"Mol. 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