title: Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways.
abstract: 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 beta-catenin level and treatment with imatinib or ionomycin, either of which blocks the beta-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the beta-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at serine 9 that caused inactivation of GSK-3beta and subsequently resulted in activation of the beta-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3beta and subsequent activation of the beta-catenin pathway.
authors.affiliation: Noevir-Keio Research Laboratory, Noevir Co., Ltd., 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Torii
authors.forename: Koji
authors.initials: K
authors.lastname: Nishizawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Masanori
authors.initials: M
authors.lastname: Katada
authors.forename: Minoru
authors.initials: M
authors.lastname: Ito
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
authors.forename: Kenzo
authors.initials: K
authors.lastname: Terashita
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020405:Dermis / Q000166:cytology* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D051153:Wnt Proteins; D051176:beta Catenin; D010768:Phosphoserine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3