Alternative titles; symbols
HGNC Approved Gene Symbol: GSKIP
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:96,363,526-96,387,290 (from NCBI)
Glycogen synthase kinase-3 (see GS3KB, 605004) is a serine/threonine kinase that phosphorylates glycogen synthase (GYS1; 138570) and regulates glycogen metabolism. It also has a major role in regulating cell fate, differentiation, and proliferation through the Wnt signaling pathway (see 606359). GSKIP is a negative regulator of GS3K kinase activity in the Wnt signaling pathway, but not in glycogen metabolism (Chou et al., 2006).
Using GSK3B in a yeast 2-hybrid screen of a human testis cDNA library, Chou et al. (2006) cloned GSKIP. The deduced 139-amino acid protein has a calculated molecular mass of 15.6 kD. GSKIP has N- and C-terminal domains that are highly conserved, particularly in vertebrates. The final 25 amino acids of the conserved C-terminal domain are similar to the GSK3B-interacting domain of axin (AXIN1; 603816). Northern blot analysis detected variable expression of a 2.1-kb GSKIP transcript in all adult and fetal tissues examined, with highest expression in adult heart, placenta, liver, and skeletal muscle. Fluorescence-tagged GSKIP was predominantly expressed in cytosol of transfected HeLa cells.
Using protein pull-down and coimmunoprecipitation analyses of cotransfected HEK293 cells, Chou et al. (2006) found that GSKIP bound GSK3B in vitro and in vivo. GSKIP also bound GSK3A (606784). The C-terminal 25 amino acids of GSKIP were the minimal unit required for binding to GSK3B. Kinetic analysis revealed a strong binding affinity between the GSKIP peptide and GSK3B. Site-directed mutagenesis revealed that ser109 and thr113, just upstream of the GSK3B-binding region of GSKIP, were major GSK3B phosphorylation targets. In vitro kinase assays showed that full-length GSKIP and the 25-amino acid GSKIP C-terminal peptide inhibited the kinase activity of GSK3B against axin and beta-catenin (CTNNB1; 116806), both of which function within the Wnt signaling pathway, but they did not inhibit GSK3B-dependent phosphorylation of glycogen synthase. Western blot analysis showed that GSKIP caused nuclear accumulation of beta-catenin, and reporter gene assays revealed that GSKIP inhibited Wnt-dependent transcription. Chou et al. (2006) concluded that GSKIP has a role in negatively regulating Wnt signaling, possibly via binding-site overlap.
Chou et al. (2006) reported that the GSKIP gene contains 3 exons. The first exon is noncoding.
Chou et al. (2006) reported that the GSKIP gene maps to chromosome 14q32.2.
Germline Variation
For a discussion of an association between germline copy number variation involving the GSKIP gene and susceptibility to familial myeloid malignancies, see 616604.
Chou, H.-Y., Howng, S.-L., Cheng, T.-S., Hsiao, Y.-L., Lieu, A.-S., Loh, J.-K., Hwang, S.-L., Lin, C.-C., Hsu, C.-M., Wang, C., Lee, C.-I, Lu, P.-J., Chou, C.-K., Huang, C.-Y., Hong, Y.-R. GSKIP is homologous to the Axin GSK3-beta interaction domain and functions as a negative regulator of GSK3-beta. Biochemistry 45: 11379-11389, 2006. [PubMed: 16981698] [Full Text: https://doi.org/10.1021/bi061147r]