title: Polo-like kinase 2, a novel ADAM17 signaling component, regulates tumor necrosis factor α ectodomain shedding.
abstract: ADAM17 (a disintegrin and metalloprotease 17) 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. 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-TNFα and TNF receptors 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 up-regulated during inflammatory conditions increasing ADAM17-mediated proteolytic events. Our findings suggest a new role for PLK2 in the regulation of inflammatory diseases by modulating ADAM17 activity.
authors: From the Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24118 Kiel, Germany.
authors: Jeanette
authors: J
authors: Schwarz
authors: Stefanie
authors: S
authors: Schmidt
authors: Olga
authors: O
authors: Will
authors: Tomas
authors: T
authors: Koudelka
authors: Kaja
authors: K
authors: Köhler
authors: Melanie
authors: M
authors: Boss
authors: Björn
authors: B
authors: Rabe
authors: Andreas
authors: A
authors: Tholey
authors: Jürgen
authors: J
authors: Scheller
authors: Dirk
authors: D
authors: Schmidt-Arras
authors: Michael
authors: M
authors: Schwake
authors: Stefan
authors: S
authors: Rose-John
authors: Athena
authors: A
authors: Chalaris
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D014409:Tumor Necrosis Factor-alpha; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: ADAM ADAMTS; ADAM17; Metalloprotease; PLK2; Phosphorylation; Shedding; Tumor Necrosis Factor (TNF)