Editors' ChoiceCancer

NIK sends mitochondria to the periphery

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Science Signaling  03 Jan 2017:
Vol. 10, Issue 460, eaam6493
DOI: 10.1126/scisignal.aam6493

The kinase NIK promotes tumor cell invasion by stimulating the translocation of mitochondria to the cell periphery.

Nuclear factor κB (NF-κB)–inducing kinase (NIK) is a constitutively active kinase that functions in immunity by stimulating noncanonical NF-κB signaling. NIK has also been implicated in tumorigenesis and metastasis. Jung et al. found that NIK stimulated the translocation of mitochondria to the leading edge of migrating cancer cells, a phenomenon that has been observed in various types of invasive cancers. NIK localized to mitochondria throughout the cytoplasm and in cytoplasmic processes in cultured glioma, breast cancer, and pancreatic cancer cells; in patient-derived glioma samples; and in mouse embryonic fibroblasts (MEFs). In cultured BT25 glioma cells, mitochondria were distributed throughout the cell body and cytoplasmic processes and exhibited predominantly anterograde movement toward the cell periphery. When the gene encoding NIK was deleted in these cells, the mitochondria adopted a perinuclear distribution and did not exhibit directional movement. Furthermore, these NIK-deficient cells exhibited reduced invasion into a collagen matrix. Overexpressing NIK stimulated both invasion and the localization of mitochondria to cytoplasmic processes. NIK localized to the outer mitochondrial membrane, where it was required for the recruitment of Drp1, a dynamin-related GTPase that promotes mitochondrial fission. The presence of NIK on mitochondria correlated with the presence of the active form of Drp1, and loss of Drp1 reduced cytokine-induced invasion in BT25 cells into a collagen matrix. IκB kinase α (IKKα), which acts downstream of NIK in noncanonical NF-κB signaling, did not associate with Drp1 in BT25 cells or in patient glioma samples and was not required for the ability of NIK to stimulate invasive behavior in MEFs. Although the authors did not determine whether Drp1 was a direct target of NIK, these results demonstrate that mitochondrial-localized NIK promotes the translocation of mitochondria to the cell periphery and stimulates invasive behavior in a manner that depends on Drp1 but is independent of NF-κB signaling.

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