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PKC Is Essential for Dishevelled Function in a Noncanonical Wnt

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PKC Is Essential for Dishevelled Function in a Noncanonical Wnt Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press PKC␦ is essential for Dishevelled function in a noncanonical Wnt pathway that regulates Xenopus convergent extension movements Noriyuki Kinoshita,1 Hidekazu Iioka, Akira Miyakoshi, and Naoto Ueno Department of Developmental Biology, National Institute for Basic Biology; Department of Molecular Biomechanics, The Graduate University for Advanced Studies, Myodaiji, Okazaki, Aichi 444-8585, Japan Protein kinase C (PKC) has been implicated in the Wnt signaling pathway; however, its molecular role is poorly understood. We identified novel genes encoding ␦-type PKC in the Xenopus EST databases. Loss of PKC␦ function revealed that it was essential for convergent extension during gastrulation. We then examined the relationship between PKC␦ and the Wnt pathway. PKC␦ was translocated to the plasma membrane in response to Frizzled signaling. In addition, loss of PKC␦ function inhibited the translocation of Dishevelled and the activation of c-Jun N-terminal kinase (JNK) by Frizzled. Furthermore, PKC␦ formed a complex with Dishevelled, and the activation of PKC␦ by phorbol ester was sufficient for Dishevelled translocation and JNK activation. Thus, PKC␦ plays an essential role in the Wnt/JNK pathway by regulating the localization and activity of Dishevelled. [Keywords:PKC␦; Xenopus; gastrulation; convergent extension; noncanonical Wnt pathway] Received April 4, 2003; revised version accepted May 1, 2003. During Xenopus gastrulation, mesodermal cells migrate transcription of target genes such as siamois and Xnr3 to the inside of the embryo and move along the blasto- (Brannon and Kimelman 1996; Carnac et al. 1996; Mc- coel roof. This movement is essential for embryonic Kendry et al. 1997). The second group of Wnts, which morphogenic processes such as the establishment of the includes Xwnt5a and Xwnt11, activates the noncanoni- three germ layers and body axes. The process involves cal Wnt signaling pathway that controls morphogenetic highly integrated cell movements. One of the important cell movements (Kuhl 2002; Tada et al. 2002). It was mechanisms for this movement is convergent extension. shown in zebrafish that mutations in Wnt11/silberbrick As convergent extension begins, cells are polarized and and Wnt5a/pipetail inhibit normal gastrulation move- aligned mediolaterally; this is followed by the intercala- ments (Rauch et al. 1997; Heisenberg et al. 2000). The tion of these polarized cells. This movement elongates noncanonical Wnt pathway branches into two cascades. the mesodermal tissue along the anteroposterior axis, One is the Wnt/JNK pathway, which involves c-Jun N- producing a driving force for gastrulation movements terminal kinase (JNK; Boutros et al. 1998; Yamanaka et (Wilson and Keller 1991; Shih and Keller 1992; Walling- al. 2002). The other is the Wnt/Ca2+ pathway (Kuhl et al. ford et al. 2002). The regulation of the convergent exten- 2000). In Drosophila, the Wnt/JNK pathway is called the sion movements is known to involve a noncanonical planer cell polarity (PCP) pathway, and it specifies cell Wnt signaling pathway. polarities in epithelial cells and other types of cells The Wnts are a family of secreted proteins that regu- (Adler 2002). late many biological processes (Cadigan and Nusse The Wnt signaling pathway is mediated by a seven- 1997). Functional analyses in Xenopus suggest that the transmembrane Wnt receptor, Frizzled, and the signal is Wnt family can be divided into two functionally distinct transmitted through a cytoplasmic protein, Dishevelled groups. The first group of Wnts induces a secondary axis (Dsh), which plays pivotal roles in both the canonical when ectopically expressed in embryos. They activate and noncanonical Wnt pathways (Boutros and Mlodzik the canonical Wnt/␤-catenin pathway and induce the 1999; Wharton 2003). In Drosophila, Dsh localizes to the membrane, and this localization is required for Dsh function (Axelrod 2001). Xenopus Dsh (Xdsh) is also 1Corresponding author. translocated from the cytoplasm to the plasma mem- E-MAIL [email protected]; FAX 81-564-55-7571. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ brane in response to a signal generated by some Frizzled gad.1101303. receptors (Yang-Snyder et al. 1996; Axelrod et al. 1998; GENES & DEVELOPMENT 17:1663–1676 © 2003 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/03 $5.00; www.genesdev.org 1663 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Kinoshita et al. Rothbacher et al. 2000). One such receptor is Xenopus induce an increase in intracellular Ca2+ (Slusarski et al. Frizzled7 (Xfz7), which is involved in the noncanonical 1997a,b). Among the PKC subfamilies, cPKC and nPKC Wnt pathway (Djiane et al. 2000; Medina and Steinbeis- are known to be activated by Ca2+ and/or diacylglycerol ser 2000; Medina et al. 2000). However, the mechanism (DAG). For this reason, we searched our Xenopus EST of this translocation and the activation of Dishevelled is database (NIBB XDB, http://Xenopus.nibb.ac.jp) to iden- not known. The signal transduction of the canonical tify PKC family members that belong to the cPKC or pathway seems to be different from that of the nonca- nPKC subfamily. We found that in addition to PKC␣ and nonical pathway, because the membrane translocation PKC␤, which have already been reported (Chen et al. of Xdsh is not required for the activation of the canonical 1988), the database included two novel cDNAs encoding Wnt pathway (Rothbacher et al. 2000). nPKC family members. The predicted amino acid se- Protein kinase C (PKC) is thought to be involved in the quences of these two PKCs had 95% identity, suggesting noncanonical Wnt signaling pathway, particularly in the that these are duplicated genes due to the tetraploidism Wnt/Ca2+ pathway, for several reasons. Xwnt5a and rat of Xenopus laevis. As described later, these two genes Frizzled2 activate the phosphatidylinositol pathway and had indistinguishable activities in the tests we per- increase the intracellular Ca2+ levels in zebrafish em- formed. These proteins are the most similar to mamma- bryos (Slusarski et al. 1997a,b). The phosphatidylinositol lian ␦-type PKC (Fig. 1A,B). Thus, we designated these pathway and Ca2+ levels are closely related to PKC acti- genes PKC␦1 and PKC␦2. It is known that the N-termi- vation. In fact, overexpression of Frizzled causes the nal regulatory domain of PKCs inhibits the kinase activ- translocation of epitope-tagged PKC␣ from the cyto- ity by masking the catalytic domain, and activators such plasm to the plasma membrane in Xenopus embryos as DAG release this autoinhibition by binding to the C1 (Sheldahl et al. 1999; Medina et al. 2000). Kuhl et al. domain (Kemp et al. 1994; Orr and Newton 1994; Nishi- (2001) showed that PKC␣ phosphorylated Dsh in vitro. zuka 1995; Newton 1997). The regulatory domain of In addition, the loss of Xfz7 function leads to a defect in Xenopus PKC␦1/2, including the C1 domain, is highly tissue separation during Xenopus gastrulation, which is homologous to that of human PKC␦, suggesting that rescued by the overexpression of PKC␣ (Winkbauer et al. these regulatory mechanisms are conserved. PKC␦ is 2001). PKC is also implicated in the Xwnt11 signaling relatively similar to PKC␪ and PKC␧, which also belong pathway for Xenopus cardiogenesis (Pandur et al. 2002) to the nPKC family. This class of PKCs is found not only and in the Dwnt4 pathway for Drosophila ovarian mor- in vertebrates, but also in sea sponges (GenBank acces- phogenesis (Cohen et al. 2002). sion no. CAA73557), Aplysia (GenBank accession no. Although much evidence suggests that PKC is in- 16975), Hydra (GenBank accession no. CAA72926), Dro- volved in the Wnt signaling pathway, the molecular sophila (GenBank accession no. NP_511171), and nema- roles of PKC in this pathway are not well understood. todes (GenBank accession no. NP_499860). Thus, the The PKC family is subdivided into three subfamilies: the nPKCs may have evolutionally conserved regulatory classical, novel, and atypical PKCs (cPKC, nPKC, and mechanisms and functions distinct from those of other aPKC, respectively). cPKC is activated by Ca2+ and dia- PKC subfamilies. cylglycerol (DAG), nPKC is activated by DAG but not by To determine the expression patterns during Xenopus Ca2+, and aPKC is not activated by these molecules (Kik- development, we performed reverse transcriptase PCR kawa et al. 1989; Bell and Burns 1991; Nishizuka 1995; (RT–PCR) using primers whose sequences were common Newton 1997). In Xenopus, cDNAs encoding PKC␣ and to PKC␦1 and PKC␦2. As shown in Figure 1C, PKC␦ was PKC␤, which belong to the cPKC subfamily, have been expressed from the two-cell stage through the tadpole isolated (Chen et al. 1988), and shown to be involved in stage. In situ hybridization using probes for PKC␦1 and neural induction (Otte et al. 1988; Otte and Moon 1992). PKC␦2 revealed that they were ubiquitously expressed However, their roles in the regulation of gastrulation (Fig. 1D). PKC␦1 and PKC␦2 were strongly expressed in movements are not clear. Thus, we searched for novel the mesoderm and ectoderm during gastrulation, indi- PKC genes that might have roles in the noncanonical cating their possible involvement in the regulation of Wnt signaling pathway. Here, we describe the identifi- gastrulation movements. cation and functional analyses of Xenopus PKC␦, which belongs to the nPKC subfamily. We demonstrate
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