Alternative titles; symbolsTIKI1HGNC Approved Gene Symbol: TRABD2ACytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:84,821,649-84,881,974 (from NC...
Alternative titles; symbols
HGNC Approved Gene Symbol: TRABD2A
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:84,821,649-84,881,974 (from NCBI)
▼ Cloning and Expression
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 and TRABD2B (614913), 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 505-amino acid human TIKI1 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.
▼ Gene Function
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 TRABD2A gene to chromosome 2p11.2 based on an alignment of the TRABD2A sequence (GenBank BC051789) with the genomic sequence (GRCh37).
▼ Animal Model
Using morpholino antisense oligonucleotides, Zhang et al. (2012) found that knockdown of Tiki1 in Xenopus embryos resulted in anterior defects and loss of forebrain structures. Knockdown of Tiki1 was accompanied by diminished expression of head organizer genes and defective head organizer function, which in turn caused deficiency in anterior-neural patterning. Tiki1 appeared to be required for organizer maintenance, but not organizer formation, which requires maternal Wnt signaling.