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. 2019 Feb 19;8(2):178. doi: 10.3390/cells8020178

Figure 4.

Figure 4

Plausible mechanisms of how TBK1/IKKε control proliferation of β-cells. A cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), a novel small molecule inhibitor of TBK1/IKKε showing effective β-cell regeneration potency, stimulates β-cell-specific proliferation. Genetic overexpression of PDE3, β-cell-enriched cyclic AMP (cAMP) hydrolyzing enzyme, and pharmacological inhibition of cAMP-dependent protein kinase A (PKA) and mechanistic target of rapamycin (mTOR) blunted PIAA-mediated β-cell regeneration, implicating that TBK1/IKKε suppress cAMP-PKA-mTOR signaling axis via PDE3 to reduce functionally relevant β-cells. As key cell cycle molecules are constrained to the cytoplasm in quiescent human β-cells and potentially also rodent β-cells, it is plausible that TBK1/IKKε inhibition drives proliferation of β-cells by translocating them including mTOR-regulated cyclins D2 and D3 into the nucleus. Additionally, phosphorylation of ERK1/2 was induced by PIAA, suggesting an involvement of the cAMP-PKA-ERK1/2 signaling axis in β-cell proliferation. OE, overexpression.