Signaling by secreted Wnt proteins plays a fundamental role in development and disease. One important aspect of Wnt regulation of development is that Wnt can function as a morphogen, inducing different cellular responses in a concentration-dependent manner. The molecular basis underlying the transduction of Wnt morphogen gradient remains elusive. The low-density-lipoprotein receptor related proteins 5 and 6 (LRP5 and LRP6) serve as Wnt co-receptors and are an essential signaling component of the canonical Wnt pathway. How LRP5/6 transduce Wnt signal is not well understood. I plan to explore whether LRP5/6 signaling relates to Wnt morphogen gradient interpretation. Recently Dr. Xi He's laboratory found that a conserved PPP(S/T)P motif, which is reiterated five times in the intracellular domain of LRP5/6, plays a key signaling role. They showed that Wnt induces the phosphorylation of a prototypic PPPSP motif, which serves as an inducible docking site for the cytoplasmic scaffolding protein Axin. I will test the hypothesis that phosphorylation of these five PPP(S/T)P motifs in LRP6 are differentially regulated in response to different Wnts and/or different Wnt ligand concentration.
| MacDonald, Bryan T; Yokota, Chika; Tamai, Keiko et al. (2008) Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J Biol Chem 283:16115-23 |
| MacDonald, Bryan T; Joiner, Danese M; Oyserman, Sivan M et al. (2007) Bone mass is inversely proportional to Dkk1 levels in mice. Bone 41:331-9 |
