A Wnt-CKIɛ-Rap1 Pathway Regulates Gastrulation by Modulating SIPA1L1, a Rap GTPase Activating Protein

SummaryNoncanonical Wnt signals control morphogenetic movements during vertebrate gastrulation. Casein kinase I epsilon (CKIɛ) is a Wnt-regulated kinase that regulates Wnt/β-catenin signaling and has a β-catenin-independent role(s) in morphogenesis that is poorly understood. Here we report the identification of a CKIɛ binding partner, SIPA1L1/E6TP1, a GAP (GTPase activating protein) of the Rap small GTPase family. We show that CKIɛ phosphorylates SIPA1L1 to reduce its stability and thereby increase Rap1 activation. Wnt-8, which activates CKIɛ, enhances the CKIɛ-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 CKIɛ also transduces Wnt/β-catenin signaling, inhibition of Rap1 does not alter β-catenin-regulated gene expression. Our data demonstrate a role for CKIɛ in noncanonical Wnt signaling and indicate that Wnt regulates morphogenesis in part through CKIɛ-mediated control of Rap1 signaling.