Polo-Like Kinase 2, a Novel ADAM17 Signaling Component, Regulates TNF{alpha} Ectodomain Shedding [Signal Transduction]

December 13th, 2013 by Schwarz, J., Schmidt, S., Will, O., Koudelka, T., Koehler, K., Boss, M., Rabe, B., Tholey, A., Scheller, J., Schmidt-Arras, D., Schwake, M., Rose-John, S., Chalaris, A.

A disintegrin and metalloprotease 17 (ADAM17) controls pro- and anti-inflammatory signaling events by promoting ectodomain shedding of cytokine-precursors and cytokine receptors. Despite the well documented substrate repertoire of ADAM17 little is known about regulatory mechanisms, leading to substrate recognition and catalytic activation. Here we report a direct interaction of the acidophilic kinase polo-like kinase 2 (PLK2, also known as SNK) with the cytoplasmic portion of ADAM17 through the C-terminal noncatalytic region of PLK2 containing the Polo-box domains (PBDs). PLK2 activity leads to ADAM17 phosphorylation at serine-794, which represents a novel phosphorylation site. Activation of ADAM17 by PLK2 results in the release of pro-TNF╬▒ and TNFRs from the cell surface and pharmacological inhibition of PLK2 leads to down-regulation of LPS-induced ADAM17-mediated shedding on primary macrophages and dendritic cells. Importantly, PLK2 expression is upregulated during inflammatory conditions increasing ADAM17-mediated proteolytic events. Our findings suggest a new role of PLK2 in the regulation of inflammatory diseases by modulating ADAM17 activity.