title: Role of the Rap2/TNIK kinase pathway in regulation of LRP6 stability for Wnt signaling.
abstract: The Wnt/β-catenin signaling pathway plays critical roles in early embryonic development, stem cell biology and human diseases including cancers. Although Rap2, a member of Ras GTPase family, is essential for the Wnt/β-catenin pathway during the body axis specification in Xenopus embryo, the mechanism underlying its regulation of Wnt signaling remains poorly understood. Here, we show that Rap2 is implicated in control of the stability of Wnt receptor, low-density lipoprotein receptor-related protein 6 (LRP6). Knockdown of Rap2 resulted in the proteasome and/or lysosome-dependent degradation of LRP6 both in the presence and absence of Wnt ligand stimulation. In line with this, constitutively active LRP6 lacking its extracellular domain, which is constitutively phosphorylated and resides in intracellular vesicles, was also degraded in the Rap2-silenced cells. In addition, Rap2 and LRP6 associated physically with each other. Furthermore, we found that TRAF2/Nck-interacting kinase (TNIK), a member of the Ste20 protein family, acts as a downstream effector of Rap2 in control of LRP6 stabilization. Consistently, TNIK could rescue the inhibitory effects of Rap2 depletion on Wnt-dependent gene transcription, reporter activation and neural crest induction. Taken together, these results suggest that Rap2 acts via TNIK to regulate the stability of LRP6 receptor for Wnt/β-catenin signaling.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Pungnap-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Park
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Seo
authors.forename: Mina
authors.initials: M
authors.lastname: Hong
authors.forename: Sun-Cheol
authors.initials: SC
authors.lastname: Choi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D000081410:Germinal Center Kinases; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081410:Germinal Center Kinases; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C000631453:TNIK protein, Xenopus; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human; D046988:Proteasome Endopeptidase Complex; C530501:RAP2A protein, Xenopus; D020668:rap GTP-Binding Proteins