M-LP/Mpv17L is a protein that was initially identified during screening of age-dependently expressed genes in mice. We have recently demonstrated that M-LP/Mpv17L-knockout (M-LP/Mpv17L-KO) in human hepatoma cells leads to a reduction of cellular cyclic nucleotide phosphodiesterase (PDE) activity, and that in vitro-synthesized M-LP/Mpv17L possesses PDE activity. These findings suggest that M-LP/Mpv17L functions as an atypical PDE, even though it has none of the well-conserved catalytic region or other structural motifs characteristic of the PDE family. In this study, we found that M-LP/Mpv17L-KO mice developed β-cell hyperplasia and improved glucose tolerance. Deficiency of M-LP/Mpv17L in islets from KO mice at early postnatal stages or siRNA-mediated suppression of M-LP/Mpv17L in rat insulinoma cells led to marked upregulation of lymphoid enhancer binding factor 1 (Lef1) and transcription factor 7 (Tcf7), key nuclear effectors in the Wnt signaling pathway, and some of the factors essential for the development and maintenance of β-cells. Moreover, at the protein level, increases in the levels of phosphorylated β-catenin and glycogen synthase kinase-3β (GSK-3β) were observed, indicating activation of the Wnt and TGF-β signaling pathways. Taken together, these findings suggest that protein kinase A (PKA)-dependent phosphorylations of β-catenin and GSK-3β, the key mediators of the Wnt and/or TGF-β signaling pathways, are the most upstream events triggering β-cell hyperplasia and improved glucose tolerance caused by M-LP/Mpv17L deficiency.
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