The Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases

The receptor tyrosine kinase (RTK) MuSK is part of the receptor complex that initiates neuromuscular junction formation in response to agrin [[1]xReceptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Valenzuela, DM, Stitt, TN, DiStefano, PS, Rojas, E, Mattsson, K, Compton, DL et al. Neuron. 1995; 15: 573–584Abstract | Full Text PDF | PubMed | Scopus (296)See all References, [2]xThe receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. DeChiara, TM, Bowen, DC, Valenzuela, DM, Simmons, MV, Poueymirou, WT, Thomas, S et al. Cell. 1996; 85: 501–512Abstract | Full Text | Full Text PDF | PubMed | Scopus (590)See all References, [3]xAgrin acts via a MuSK receptor complex. Glass, DJ, Bowen, DC, Stitt, TN, Radziejewski, C, Bruno, J, Ryan, TE et al. Cell. 1996; 85: 513–523Abstract | Full Text | Full Text PDF | PubMed | Scopus (493)See all References]. MuSK, as well as the related orphan RTK-like proteins Ror1 and Ror2 [4xA novel family of cell surface receptors with tyrosine kinase-like domain. Masiakowski, P and Carroll, RD. J Biol Chem. 1992; 267: 26181–26190PubMedSee all References][4], and their homologs in lower organisms, have an extracellular region composed of varying combinations of immunoglobulin and Kringle domains, but they all also have a domain defined by a pattern of 10 cysteine residues.We have noticed that the spacing of cysteines, and a number of other amino acids, is shared between this domain and a cysteine-rich domain (CRD) that serves as the ligand-binding portion of the Frizzled (Fz) family of seven-pass transmembrane receptors for the Wnt signaling molecules [5xA new member of the frizzled family from Drosophila functions as a Wingless receptor. Bhanot, P, Brink, M, Samos, CH, Hsieh, JC, Wang, Y, Macke, JP et al. Nature. 1996; 382: 225–230Crossref | PubMed | Scopus (990)See all References][5]. As seen in other receptor families, the Wnt-binding domain can also be a part of secreted Frizzled-related proteins (sFRPs) [6xA family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Rattner, A, Hsieh, JC, Smallwood, PM, Gilbert, DJ, Copeland, NG, Jenkins, NA, and Nathans, J. Proc Natl Acad Sci USA. 1997; 94: 2859–2863Crossref | PubMed | Scopus (404)See all References][6].The Fz CRD-like sequences have also been identified in Smoothened (Smo), as well as in the α1 chain of type XVIII collagen (Col18), and carboxypeptidase Z (CPZ). Smo is the signaling partner in the Sonic hedgehog (Shh) receptor system. Smo is inactivated by unoccupied Patched (Ptc) protein. Binding of Shh to Ptc relieves this inhibition. The similarity between Smo and Fz, including the CRD, prompted a suggestion [7xPatching up Hedgehog. Nusse, R. Nature. 1996; 384: 119–120Crossref | PubMed | Scopus (15)See all References][7] that the activity of Smo may in addition be modulated by a Wnt-related ligand, though no support for this possibility has been presented.Alternatively, the 10-cysteine domain found in these diverse proteins may be thought of as a general module for protein–protein interactions, evolving in different cases to bind very different counterparts (just like immunoglobulin domains). A computer alignment of the CRDs from representative proteins (Figure 1Figure 1) shows that the Wnt-binding Fz receptors and sFRPs form a distinct group, well separated from the Smo and MuSK/Ror receptors. Thus, determination of the binding specificity of CRDs in these receptors, as well as in Col18 and CPZ, seems likely to reveal new binding capabilities of the 10-cysteine module.Figure 1(a) Multiple sequence alignment of 10-cysteine domains and (b) a phylogenetic tree showing the clustering relationships used to create the alignment. The sequences were downloaded through NCBI Entrez and processed using the programs in the GCG Wisconsin Package [8xSee all References][8].View Large Image | View Hi-Res Image | Download PowerPoint Slide