Transmembrane Protein 198 Promotes LRP6 Phosphorylation and Wnt Signaling Activation

Abstract

Wnt/␤-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.

Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells

“…Several protein kinases, including glycogen synthase kinase-3 and casein kinase-1γ, have been shown to phosphorylate this Wnt coreceptor (27). A recent study showed that transmembrane protein 198 can promote LRP6 phosphorylation and Wnt signaling activation by recruitment of casein kinase family proteins (28). Another report showed that salinomycin is able to overcome multidrug resistance mediated by the ATPbinding cassette transporter p-glycoprotein 170 (29).…”

Negative feedback regulation of Wnt signaling via N-linked fucosylation in zebrafish

“…Consistent with this notion, slc35c1 OE are more sensitive to elevated Lrp6 than wild-type embryos. Previous studies of Lrp6 mediated regulation of Wnt signaling indicate that the presence of Lrp6 does not necessarily result in Wnt activation because Lrp6 must be phosphorylated and internalized to activate Wnt signaling (Liang et al, 2011) and reviewed in (Cruciat & Niehrs, 2013). In addition, Lrp6 is known to form higher order complexes with multiple factors that can influence the composition of the higher order complexes as well as whether or not the Wnt signal is transduced.…”

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

“…Tiam1-C1199 was subcloned into the pEGFP-N1 vector to obtain Tiam1-C1199-GFP. CK1 constructs have been described previously (34). Five fragments of Tiam, 1named Tiam1-A (aa 1-392), Tiam1-B (aa 393-750), Tiam1-C (aa 751-1000), Tiam1-D (aa 1001-1250), and Tiam1-E (aa 1251-1591) were subcloned into the pcDNA 3.1 vector fused with an N-terminal Myc tag.…”