NIK, a Novel Regulator of Mitochondrial Dynamics and Invasion in High-Grade Glioma
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NF-κB inducing kinase (NIK, also known as MAP3K14) is a serine/threonine protein-kinase that is crucial for activation of the non-canonical NF-κB signaling pathway. Although NIK has been shown to promote tumorigenesis in several cancers by increasing cell proliferation and survival, the molecular mechanisms underlying the role of NIK in regulating glioma pathogenesis remain poorly understood. While NIK is described as being primarily cytosolic, in this study, we found that a discrete pool of NIK is predominantly localized to mitochondria in patient-derived glioma cells, ex vivo tumor tissue, and mouse embryonic fibroblasts (MEFs). Depletion of NIK using CRISPR/Cas9-mediated genome editing causes diminished invasion in three-dimensional collagen matrices and also results in morphological alterations of mitochondria, which appear entangled and clustered in perinuclear regions. Analysis of mitochondrial trafficking in living cells revealed that NIK promoted mitochondria velocity and subcellular distribution to the leading edge of migrating glioma cells. Importantly, NIK enhances mitochondrial recruitment of dynamin related protein 1 (Drp1), a key component of mitochondrial fission machinery, to promote mitochondrial fragmentation and glioma cell invasion. NIK interacts with Drp1 at mitochondria, rather than in the cytoplasm. Particularly, NIK accumulated transiently on dividing mitochondria, where it binds to Drp1 at mitochondrial constriction at fission sites. Notably, NIK regulation of mitochondrial dynamics, glioma cell invasion, and tumor growth requires its kinase activity, but occurs independently of its established downstream targets, IĸB kinase (IKK) ɑ/ß and NF-κB activation. Additionally, NIK kinase activity is critical to promote phosphorylation of Drp1 at serine 616, which is important for its fission-promoting function. Our results establish a new paradigm for IKK-independent NIK signaling at mitochondria and significantly expand the current dogma that NIK is mainly 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.
Jung, Jiung (2018). NIK, a Novel Regulator of Mitochondrial Dynamics and Invasion in High-Grade Glioma. Doctoral dissertation, Texas A & M University. Available electronically from