title: NIK/MAP3K14 Regulates Mitochondrial Dynamics and Trafficking to Promote Cell Invasion.
abstract: Although the role of NF-κB-inducing kinase (NIK) in immunity is well established, its relevance in cancer is just emerging. Here we describe novel functions for NIK in regulating mitochondrial dynamics and motility to promote cell invasion. We show that NIK is localized to mitochondria in cancer cell lines, ex vivo tumor tissue, and mouse embryonic fibroblasts (MEFs). NIK promotes mitochondrial fission, velocity, and directional migration, resulting in subcellular distribution of mitochondria to the periphery of migrating cells. Moreover, NIK is required for recruitment of Drp1 to mitochondria, forms a complex with Drp1, and regulates Drp1 phosphorylation at Ser-616 and dephosphorylation at Ser-637. Consistent with a role for NIK in regulating mitochondrial dynamics, we demonstrate that Drp1 is required for NIK-dependent, cytokine-induced invasion. Importantly, using MEFs, we demonstrate that the established downstream mediators of NIK signaling, IκB kinase α/β (IKKα/β) and NF-κB, are not required for NIK to regulate cell invasion, Drp1 mitochondrial localization, or mitochondrial fission. Our results establish a new paradigm for IKK-independent NIK signaling and significantly expand the current dogma that NIK is predominantly cytosolic and exclusively regulates NF-κB activity. Overall, these findings highlight the importance of NIK in tumor pathogenesis and invite new therapeutic strategies that attenuate mitochondrial dysfunction through inhibition of NIK and Drp1.
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Ji-Ung
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Sowndharya
authors.initials: S
authors.lastname: Ravi
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Dong W
authors.initials: DW
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Kassandra
authors.initials: K
authors.lastname: McFadden
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Kamradt
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College Station, TX 77807-3260, USA; The Texas Brain and Spine Institute, Bryan, TX 77807, USA.
authors.forename: L Gerard
authors.initials: LG
authors.lastname: Toussaint
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA; The Texas Brain and Spine Institute, Bryan, TX 77807, USA. Electronic address: sitcheran@tamhsc.edu.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sitcheran
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
keywords: Drp1; IKK; MAP3K14; NF-κB-inducing kinase; NIK; fission; glioma; invadopodia; invasion; mitochondria