A Wnt-CKIε-Rap1 pathway regulates gastrulation by modulating SIPA1L1, a Rap GTPase activating protein

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