title: The TRAF3 adaptor protein drives proliferation of anaplastic large cell lymphoma cells by regulating multiple signaling pathways.
abstract: T cells devoid of tumor necrosis factor receptor associated factor-3 (Traf3) exhibit decreased proliferation, sensitivity to apoptosis, and an improper response to antigen challenge. We therefore hypothesized that TRAF3 is critical to the growth of malignant T cells. By suppressing TRAF3 protein in different cancerous T cells, we found that anaplastic large cell lymphoma (ALCL) cells require TRAF3 for proliferation. Since reducing TRAF3 results in aberrant activation of the noncanonical nuclear factor-κB (NF-κB) pathway, we prevented noncanonical NF-κB signaling by suppressing RelB together with TRAF3. This revealed that TRAF3 regulates proliferation independent of the noncanonical NF-κB pathway. However, suppression of NF-κB-inducing kinase (NIK) along with TRAF3 showed that high levels of NIK have a partial role in blocking cell cycle progression. Further investigation into the mechanism by which TRAF3 regulates cell division demonstrated that TRAF3 is essential for continued PI3K/AKT and JAK/STAT signaling. In addition, we found that while NIK is dispensable for controlling JAK/STAT activity, NIK is critical to regulating the PI3K/AKT pathway. Analysis of the phosphatase and tensin homolog (PTEN) showed that NIK modulates PI3K/AKT signaling by altering the localization of PTEN. Together our findings implicate TRAF3 as a positive regulator of the PI3K/AKT and JAK/STAT pathways and reveal a novel function for NIK in controlling PI3K/AKT activity. These results provide further insight into the role of TRAF3 and NIK in T cell malignancies and indicate that TRAF3 differentially governs the growth of B and T cell cancers.
authors.affiliation: Division of Pharmacology and Toxicology and The Center for Molecular and Cellular Toxicology; College of Pharmacy and The Institute for Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA.
authors.forename: Israel
authors.initials: I
authors.lastname: Muro
authors.affiliation: Division of Pharmacology and Toxicology and The Center for Molecular and Cellular Toxicology; College of Pharmacy and The Institute for Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Fang
authors.affiliation: Division of Pharmacology and Toxicology and The Center for Molecular and Cellular Toxicology; College of Pharmacy and The Institute for Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA.
authors.forename: Kacie A
authors.initials: KA
authors.lastname: Gardella
authors.affiliation: Division of Pharmacology and Toxicology and The Center for Molecular and Cellular Toxicology; College of Pharmacy and The Institute for Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA.
authors.forename: Indra M
authors.initials: IM
authors.lastname: Mahajan
authors.affiliation: Division of Pharmacology and Toxicology and The Center for Molecular and Cellular Toxicology; College of Pharmacy and The Institute for Cellular and Molecular Biology; The University of Texas at Austin; Austin, TX USA.
authors.forename: Casey W
authors.initials: CW
authors.lastname: Wright
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*
chemical_list: D048008:TNF Receptor-Associated Factor 3
keywords: JAK/STAT; NF-κB; NIK; PI3K/AKT; TRAF3
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