DEV01117 Supplemental Figures

Files in this Data Supplement:

• Figure S1 -

  Fig. S1. Alignment of Drosophila Arrow, and human LRP5 and LRP6 intracellular domains. Asterisk indicates identical residues; colon (:) indicates conserved residues; and stop (.) indicates semi-conserved residues. PPP(S/T)P motifs are boxed. The di-leucine and YRxY motifs, which may be involved in receptor internalization, are marked by arrowheads and are underlined, respectively. Modified with permission from Tamai et al. (Tamai et al., 2004).

• Figure S2 -

  Fig. S2. Schematic diagrams of Dkk, Wise and Krm families, which are only found in vertebrates. (A) Dkks. Four Dkks have been identified in Xenopus, mouse and human. Dkk1, Dkk2 and Dkk4 bind and antagonize Lrp6, and probably Lrp5. Dkk2 may weakly activate b-catenin signaling in some assays. Dkk3 neither binds nor affects Lrp6 signaling. CYS1 and CYS2 represent conserved cysteine-rich domains 1 and 2, respectively. The CYS2 domain is involved in binding and antagonizing Lrp6, and in binding to Krm (Mao and Niehrs, 2003). (B) Wise and SOST. Wise has been identified in Xenopus, chick, mouse, rat and human, and is identical to Ectodin and Usag1 (uterine sensitization-associated gene 1) (Simmons and Kennedy, 2002). Wise binds to and antagonizes signaling by Lrp6, although Wise alone may weakly activate b-catenin signaling in some circumstances. SOST is mutated in the human disease sclerosteosis (skeleton overgrowth/high bone mass). Whether SOST binds to and antagonizes signaling by LRP5/LRP6 is unknown. Wise/Ectodin and SOST also bind and antagonize signaling by BMPs. CT, cysteine-knot domain. (C) Krm1 and Krm2. Krm1 and Krm2 are found in Xenopus, mouse and human, and both can bind Dkk1 and Dkk2 (via the Dkk CYS2 domain), but not Dkk3. Either Krm1 or Krm2 can cooperate with Dkk1 in antagonizing Wnt/Lrp6 signaling, perhaps by promoting Lrp6 internalization, but the Krm intracellular domain is neither conserved nor required for antagonizing Lrp6. Extracellular Kringle (KR), WSC and CUB domains are conserved and required for Dkk binding.