Alternative titles; symbols
HGNC Approved Gene Symbol: TRABD2B
Cytogenetic location: 1p33 Genomic coordinates (GRCh38): 1:47,760,528-47,997,385 (from NCBI)
By searching a database for sequences similar to Xenopus Tiki1, which was named after the large-headed humanoid in Polynesian mythology, Zhang et al. (2012) identified human TRABD2A (614912) and TRABD2B, which they called TIKI1 and TIKI2, respectively. Most vertebrates, including Xenopus and zebrafish, have 2 TIKI genes, whereas invertebrates and bacteria have a single TIKI ortholog. The deduced 517-amino acid human TIKI2 protein contains an N-terminal signal peptide, followed by a conserved 340-amino acid TIKI ectodomain and a C-terminal transmembrane domain. Xenopus and human TIKI proteins were expressed on plasma and internal membranes following transfection of HEK293T or HeLa cells, and their ectodomains were released into the culture medium.
Using a functional screen, Zhang et al. (2012) found that Tiki1 was required for anterior-posterior patterning and Wnt (see WNT3A; 606359) signaling in Xenopus embryos. Overexpression of Tiki1 in Xenopus embryos caused head enlargement. Full-length Xenopus Tiki2, human TIKI1 and TIKI2, and the secreted N-terminal ectodomains of all TIKI proteins functioned as Wnt antagonists in Xenopus embryos, HEK293T cells, and mouse L cells. Depletion of TIKI2 in HEK293T cells via small interfering RNA enhanced WNT3A-induced reporter expression, and the effect was reversed by expression of TIKI1. WNT3A produced in L cells and HEK293T cells was secreted into the culture medium in the presence of TIKI1 and TIKI2; however, secreted WNT3A lacked 8 N-terminal amino acids essential for Wnt activity, and it formed large inactive extracellular aggregates linked by intermolecular disulfide bonds. Cleavage of Wnt8 (see WNT8A; 606360) was also observed following Tiki1 and Tiki2 expression in Xenopus embryos. In contrast, knockdown of TIKI2 in HEK293T cells reduced WNT3A cleavage. The proteolytic activity associated with TIKI2 had a pH optimum between pH 7 and 9, was sensitive to a metalloprotease inhibitor that chelates divalent cations, and was enhanced by Co(2+) and Mn(2+). Zhang et al. (2012) concluded that the metalloprotease activity associated with TIKI1 and TIKI2 antagonizes WNT3A signaling.
Hartz (2012) mapped the TRABD2B gene to chromosome 1p33 based on an alignment of the TRABD2B sequence (GenBank AK090467) with the genomic sequence (GRCh37).
Hartz, P. A. Personal Communication. Baltimore, Md. 11/2/2012.
Zhang, X., Abreu, J. G., Yokota, C., MacDonald, B. T., Singh, S., Coburn, K. L. A., Cheong, S.-M., Zhang, M. M., Ye, Q.-Z., Hang, H. C., Steen, H., He, X. Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell 149: 1565-1577, 2012. [PubMed: 22726442] [Full Text: https://doi.org/10.1016/j.cell.2012.04.039]