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Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2
Author(s) -
Yamamoto Hiroyuki,
Yoo Sa Kan,
Nishita Michiru,
Kikuchi Akira,
Minami Yasuhiro
Publication year - 2007
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01128.x
Subject(s) - gsk 3 , biology , wnt signaling pathway , phosphorylation , gsk3b , microbiology and biotechnology , tyrosine phosphorylation , signal transduction , small interfering rna , biochemistry , transfection , gene
The receptor tyrosine kinase Ror2 plays important roles in mediating non‐canonical Wnt5a signaling by activating the Wnt–JNK pathway and inhibiting the β‐catenin–TCF pathway. It has been shown that Ror2 is phosphorylated and activated by casein kinase Iɛ when both molecules are over‐expressed in cultured cells. However, it remains unknown whether or not Ror2 is phosphorylated upon Wnt5a stimulation. Here we show that Ror2 is phosphorylated on serine/threonine residues upon stimulation of cultured cells, expressing Ror2 endogenously, with Wnt5a, but not Wnt3a. It was found that treatment of cells with glycogen synthase kinase‐3 (GSK‐3) inhibitors (LiCl and SB216763) or small interfering RNAs (siRNAs) for GSK‐3 (mainly GSK‐3α) can inhibit Wnt5a‐induced phosphorylation of Ror2. Immunoprecipitated Ror2 can also be phosphorylated by purified GSK‐3α or GSK‐3β in vitro , and ectopic co‐expression of Ror2 and GSK‐3 (mainly GSK‐3α) in cultured cells results in Ror2 phosphorylation, irrespective of Wnt5a, that is sensitive to SB216763. These results indicate that GSK‐3 is involved in Wnt5a‐induced phosphorylation of Ror2. Moreover, it was found that Wnt5a‐induced cell migration can be inhibited by SB216763 or by siRNA‐mediated suppression of GSK‐3α (and GSK‐3β) expression, further emphasizing the role(s) of GSK‐3 in Wnt5a‐induced signaling.