title: A Wnt-CKIvarepsilon-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein.
abstract: Noncanonical Wnt signals control morphogenetic movements during vertebrate gastrulation. Casein kinase I epsilon (CKIvarepsilon) is a Wnt-regulated kinase that regulates Wnt/beta-catenin signaling and has a beta-catenin-independent role(s) in morphogenesis that is poorly understood. Here we report the identification of a CKIvarepsilon binding partner, SIPA1L1/E6TP1, a GAP (GTPase activating protein) of the Rap small GTPase family. We show that CKIvarepsilon phosphorylates SIPA1L1 to reduce its stability and thereby increase Rap1 activation. Wnt-8, which activates CKIvarepsilon, enhances the CKIvarepsilon-dependent phosphorylation and degradation of SIPA1L1. In early Xenopus or zebrafish development, inactivation of the Rap1 pathway results in abnormal gastrulation and a shortened anterior-posterior axis. Although CKIvarepsilon also transduces Wnt/beta-catenin signaling, inhibition of Rap1 does not alter beta-catenin-regulated gene expression. Our data demonstrate a role for CKIvarepsilon in noncanonical Wnt signaling and indicate that Wnt regulates morphogenesis in part through CKIvarepsilon-mediated control of Rap1 signaling.
authors.affiliation: Center for Children and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Tsai
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Amack
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Gao
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047108:Embryonic Development / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005775:Gastrula / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; C519091:SIPA1L1 protein, zebrafish; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495248:wnt8a protein, Xenopus; D048149:Casein Kinase 1 epsilon; D020827:rap1 GTP-Binding Proteins