Polo-like kinase 2, a novel ADAM17 signaling component, regulates tumor necrosis factor α ectodomain shedding

Area of Science:

• Molecular Biology
• Immunology
• Biochemistry

Background:

• ADAM17 (a disintegrin and metalloprotease 17) is crucial for inflammatory signaling via ectodomain shedding of cytokines and receptors.
• Mechanisms regulating ADAM17 substrate recognition and activation remain incompletely understood.

Purpose of the Study:

• To investigate the regulatory mechanisms controlling ADAM17 activity.
• To identify novel interactions and post-translational modifications of ADAM17.

Main Methods:

• Investigated the interaction between Polo-like kinase 2 (PLK2) and ADAM17 using biochemical assays.
• Identified a novel phosphorylation site (serine 794) on ADAM17 induced by PLK2.
• Assessed the functional consequences of PLK2-mediated ADAM17 activation on cytokine shedding in macrophages and dendritic cells.

Main Results:

• Direct interaction between PLK2 and the cytoplasmic domain of ADAM17 was demonstrated.
• PLK2 phosphorylates ADAM17 at serine 794, enhancing its catalytic activity.
• PLK2 activation leads to increased shedding of pro-TNFα and TNF receptors; PLK2 inhibition reduces LPS-induced shedding.

Conclusions:

• PLK2 acts as a novel activator of ADAM17 through direct phosphorylation.
• PLK2 expression is upregulated during inflammation, correlating with increased ADAM17 activity.
• PLK2 represents a potential therapeutic target for modulating ADAM17-driven inflammatory processes.