Tsai I-Chun, Amack Jeffrey D, Gao Zhong-Hua, Band Vimla, Yost H Joseph, Virshup David M
Center for Children and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Dev Cell. 2007 Mar;12(3):335-47. doi: 10.1016/j.devcel.2007.02.009.
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.
非经典Wnt信号在脊椎动物原肠胚形成过程中控制形态发生运动。酪蛋白激酶Iε（CKIε）是一种受Wnt调节的激酶，它调节Wnt/β-连环蛋白信号传导，并且在形态发生中具有尚未完全了解的不依赖β-连环蛋白的作用。在此，我们报告了一种CKIε结合蛋白SIPA1L1/E6TP1的鉴定，它是Rap小GTP酶家族的一种GAP（GTP酶激活蛋白）。我们发现CKIε使SIPA1L1磷酸化以降低其稳定性，从而增加Rap1的激活。激活CKIε的Wnt-8增强了CKIε依赖的SIPA1L1磷酸化和降解。在非洲爪蟾或斑马鱼的早期发育中，Rap1信号通路的失活导致原肠胚形成异常和前后轴缩短。虽然CKIε也转导Wnt/β-连环蛋白信号，但对Rap1的抑制并不改变β-连环蛋白调节的基因表达。我们的数据证明了CKIε在非经典Wnt信号传导中的作用，并表明Wnt部分通过CKIε介导的Rap1信号控制来调节形态发生。
