TY - JOUR
T1 - Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways
AU - Torii, Kosuke
AU - Nishizawa, Koji
AU - Kawasaki, Aya
AU - Yamashita, Yuki
AU - Katada, Masanori
AU - Ito, Minoru
AU - Nishimoto, Ikuo
AU - Terashita, Kenzo
AU - Aiso, Sadakazu
AU - Matsuoka, Masaaki
PY - 2008/7/1
Y1 - 2008/7/1
N2 - Wnts are secreted glycoproteins that control diverse biological processes, such as proliferation, differentiation, and apoptosis. We here found that Wnt5a inhibited apoptosis induced by serum deprivation in primary-cultured human dermal fibroblasts. Anti-apoptotic activity of Wnt5a was not inhibited by a dickkopf-1 (DKK), which blocks the canonical Wnt pathway. On the other hand, loss of function of protein kinase A (PKA), induced by treatment with PKA inhibitors, siRNA-mediated knocking down of endogenous PKA catalytic subunits, or enforced expression of dominant-negative PKA inhibited the Wnt5a anti-apoptotic activity, indicating the involvement of PKA in the Wnt5a anti-apoptotic activity. In agreement, phosphorylation levels of a cAMP response element binding protein (CREB), a representative downstream effector of PKA, the activation of which is known to lead to the pro-survival effects, was elevated by Wnt5a. In addition, Wnt5a increased the nuclear β-catenin level and treatment with imatinib or ionomycin, either of which blocks the β-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the β-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine 9 that caused inactivation of GSK-3β and subsequently resulted in activation of the β-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3β and subsequent activation of the β-catenin pathway.
AB - Wnts are secreted glycoproteins that control diverse biological processes, such as proliferation, differentiation, and apoptosis. We here found that Wnt5a inhibited apoptosis induced by serum deprivation in primary-cultured human dermal fibroblasts. Anti-apoptotic activity of Wnt5a was not inhibited by a dickkopf-1 (DKK), which blocks the canonical Wnt pathway. On the other hand, loss of function of protein kinase A (PKA), induced by treatment with PKA inhibitors, siRNA-mediated knocking down of endogenous PKA catalytic subunits, or enforced expression of dominant-negative PKA inhibited the Wnt5a anti-apoptotic activity, indicating the involvement of PKA in the Wnt5a anti-apoptotic activity. In agreement, phosphorylation levels of a cAMP response element binding protein (CREB), a representative downstream effector of PKA, the activation of which is known to lead to the pro-survival effects, was elevated by Wnt5a. In addition, Wnt5a increased the nuclear β-catenin level and treatment with imatinib or ionomycin, either of which blocks the β-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the β-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine 9 that caused inactivation of GSK-3β and subsequently resulted in activation of the β-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3β and subsequent activation of the β-catenin pathway.
KW - Apoptosis
KW - PKA
KW - Wnt5a
KW - β-catenin
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U2 - 10.1016/j.cellsig.2008.02.013
DO - 10.1016/j.cellsig.2008.02.013
M3 - Article
C2 - 18407462
AN - SCOPUS:43049178193
SN - 0898-6568
VL - 20
SP - 1256
EP - 1266
JO - Cellular Signalling
JF - Cellular Signalling
IS - 7
ER -