TNFR1 signaling is positively regulated by Jak-2 and c-Src via tyrosine phosphorylation

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dc.contributor.authorHapil Zevkliler, Fatma Zehra
dc.contributor.authorCopuroglu, Fatma Ece
dc.contributor.authorErtosu, Mustafa Gokhan
dc.contributor.authorMert, Ufuk
dc.contributor.authorOzes, Derya
dc.contributor.authorOzes, Osman Nidai
dc.date.accessioned2024-08-31T07:50:33Z
dc.date.available2024-08-31T07:50:33Z
dc.date.issued2024
dc.departmentEge Üniversitesien_US
dc.description.abstractBackground/aim: Tumor necrosis factor alpha (TNF alpha, a.k.a. TNF) is a pleiotropic cytokine that exerts most of its effects through type 1 TNF receptor (TNFR1). Following TNF binding, TNFR1 recruits TRADD (tumor necrosis factor receptor type 1 -associated DEATH domain). This interaction triggers formation of signalosome complexes which have been claimed to induce apoptosis (via downstream caspase activations), inflammation (via NF-kappaB) and stress pathways (JNK & p38). However, the mechanism underlying TNFinduced ERK and AKT activation is not completely revealed. TNFR1 is known to constitutively bind c-Src and JAK2, and these enzymes were previously demonstrated to modulate TNF signaling. Therefore, we hypothesized that TNFR1 could be tyrosine phosphorylated by JAK2 and/or c-Src and TNF-induced ERK and Akt activation may be mediated by this phosphorylation. Materials and methods: Site -directed mutagenesis (SDM) was performed to substitute the two putative Tyrosine phosphorylation sites on TNFR1 (Y360 and Y401) with alanine (A) or with aspartic acid (D), to inhibit or mimic constitutive phosphorylation, respectively. In 293T cells transfected with mutated or wild type TNFR1, ERK and Akt activations were determined by western blot. TNFR1 interaction with c-Src, JAK2, p85 and Grb2 was examined by co-IP. NF-kB activation was measured by luciferase assay, while proliferation was measured by MTT and apoptosis was evaluated by colorimetric caspase 8/3 assays. For determination of necrosis rates, cellular DNA fragmentation ELISA was performed. Results: In this report, we show that TNFR1 is phosphorylated by JAK2 tyrosine kinase at Y401 and by c-Src at Y360 and Y401. Phosphorylation of Y360 and Y401 augments the interaction of Grb2 and PI3Kp85 with TNFR1. We also demonstrate that phosphomimetic mutations of Y360D and Y401D enhance ERK and Akt activation. Conclusion: TNFR1 is tyrosine phosphorylated by both c-Src and JAK2, triggering a noncanonical pathway, that activates ERK and Akt.en_US
dc.description.sponsorshipScientific and Technological Research Council of Turkiye (TUBITAK) [113s335]en_US
dc.description.sponsorshipThis work was supported by The Scientific and Technological Research Council of Turkiye (TUBITAK) with grant number 113s335.en_US
dc.identifier.doi10.55730/1300-0152.2677
dc.identifier.issn1300-0152
dc.identifier.issn1303-6092
dc.identifier.issue1en_US
dc.identifier.pmid38665776en_US
dc.identifier.scopus2-s2.0-85186565563en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.urihttps://doi.org/10.55730/1300-0152.2677
dc.identifier.urihttps://hdl.handle.net/11454/105283
dc.identifier.volume48en_US
dc.identifier.wosWOS:001178934500007en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherTubitak Scientific & Technological Research Council Turkeyen_US
dc.relation.ispartofTurkish Journal of Biologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmz20240831_Uen_US
dc.subjectTnfen_US
dc.subjectTnfr1en_US
dc.subjectJak2en_US
dc.subjectC-Srcen_US
dc.subjectErken_US
dc.subjectAkten_US
dc.titleTNFR1 signaling is positively regulated by Jak-2 and c-Src via tyrosine phosphorylationen_US
dc.typeArticleen_US

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