Pyrvinium pamoate does not activate protein kinase CK1, but promotes Akt/PKB down-regulation and GSK3 activation

It has been reported that Pyrvinium Pamoate (PyrPam), an FDA approved anthelminthic drug is a potent inhibitor of Wnt signaling by a mechanism which implies the direct activation of protein kinase CK1α. Here we present data ruling out any direct stimulatory effect of PyrPam on CK1, by showing that neither the catalytic activity of CK1α nor those of its isoforms δ and γ1 are significantly affected by PyrPam when tested with the aid of specific peptide and protein substrates. Accordingly, cell treatment with PyrPam has no significant effect on the phosphorylation of β-catenin Ser-45. By contrast the phosphorylation of β-catenin Thr-41 is increased upon cell treatment with PyrPam, through a mechanism that implies the upstream dephosphorylation of Akt/PKB and of GSK3. It can be concluded from our work that PyrPam is not a bona fide activator of CK1, its perturbation of cell signaling pathways being mediated by a complex mechanism initiated by a drop in Akt/PKB phosphorylation whose down-regulation promotes reduced phosphorylation and activation of GSK3. Consistent with this, lysates of cells treated with PyrPam display enhanced protein phosphorylation which is unaffected by CK1 inhibition while disappearing upon inhibition of GSK3. Our data are consistent with the observation that PyrPam ultimately inhibits Wnt signaling despite its lack of efficacy on CK1.

Source: BJ Signal - February 26, 2013 Category: Biochemistry Authors: A Venerando, C Girardi, M Ruzzene, L A Pinna Tags: BJ Signal Source Type: research