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

Abstract

The receptor tyrosine kinase (RTK) MuSK is part of the receptor complex that initiates neuromuscular junction formation in response to agrin [1Valenzuela DM Stitt TN DiStefano PS Rojas E Mattsson K Compton DL et al.Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury.Neuron. 1995; 15 (96009854): 573-584Abstract Full Text PDF PubMed Scopus (345) Google Scholar, 2DeChiara TM Bowen DC Valenzuela DM Simmons MV Poueymirou WT Thomas S et al.The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo.Cell. 1996; 85 (96222293): 501-512Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar, 3Glass DJ Bowen DC Stitt TN Radziejewski C Bruno J Ryan TE et al.Agrin acts via a MuSK receptor complex.Cell. 1996; 85 (96222294): 513-523Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar]. MuSK, as well as the related orphan RTK-like proteins Ror1 and Ror2 [[4]Masiakowski P Carroll RD A novel family of cell surface receptors with tyrosine kinase-like domain.J Biol Chem. 1992; 267 (93100347): 26181-26190Abstract Full Text PDF PubMed Google Scholar], 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 [[5]Bhanot P Brink M Samos CH Hsieh JC Wang Y Macke JP et al.A new member of the frizzled family from Drosophila functions as a Wingless receptor.Nature. 1996; 382: 225-230Crossref PubMed Scopus (1191) Google Scholar]. As seen in other receptor families, the Wnt-binding domain can also be a part of secreted Frizzled-related proteins (sFRPs) [[6]Rattner A Hsieh JC Smallwood PM Gilbert DJ Copeland NG Jenkins NA Nathans J A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors.Proc Natl Acad Sci USA. 1997; 94 (97250455): 2859-2863Crossref PubMed Scopus (483) Google Scholar]. 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 [[7]Nusse R Patching up Hedgehog.Nature. 1996; 384 (97064164): 119-120Crossref PubMed Scopus (16) Google Scholar] 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 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. Program Manual for the Wisconsin Package V.9. 1996, Genetics Computer Group http//www.gcg.com P Masiakowski and GD Yancopoulos, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591–6707, USA.