title: Transmembrane protein 198 promotes LRP6 phosphorylation and Wnt signaling activation.
abstract: Wnt/β-catenin signaling is fundamental in embryogenesis and tissue homeostasis in metazoans. Upon Wnt stimulation, cognate coreceptors LRP5 and LRP6 ([LRP5/6] low-density lipoprotein receptor-related proteins 5 and 6) are activated via phosphorylation at key residues. Although several kinases have been implicated, the LRP5/6 activation mechanism remains unclear. Here, we report that transmembrane protein 198 (TMEM198), a previously uncharacterized seven-transmembrane protein, is able to specifically activate LRP6 in transducing Wnt signaling. TMEM198 associates with LRP6 and recruits casein kinase family proteins, via the cytoplasmic domain, to phosphorylate key residues important for LRP6 activation. In mammalian cells, TMEM198 is required for Wnt signaling and casein kinase 1-induced LRP6 phosphorylation. During Xenopus embryogenesis, maternal and zygotic tmem198 mRNAs are widely distributed in the ectoderm and mesoderm. TMEM198 is required for Wnt-mediated neural crest formation, antero-posterior patterning, and particularly engrailed-2 expression in Xenopus embryos. Thus, our results identified TMEM198 as a membrane scaffold protein that promotes LRP6 phosphorylation and Wnt signaling activation.
authors.affiliation: Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Cristina-Maria
authors.initials: CM
authors.lastname: Cruciat
authors.forename: Shunji
authors.initials: S
authors.lastname: Jia
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tong
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Tao
authors.forename: Dierk
authors.initials: D
authors.lastname: Ingelfinger
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
mesh_terms: D000818:Animals; D019521:Body Patterning; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology* / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; C560428:TMEM198 protein, Xenopus; C560429:TMEM198 protein, human; D051153:Wnt Proteins; D029867:Xenopus Proteins