Alternative titles; symbols
HGNC Approved Gene Symbol: COPS2
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38): 15:49,122,727-49,155,599 (from NCBI)
COPS2 is a subunit of the conserved COP9 signalosome (Min et al., 2005).
Thyroid hormone receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. They must specifically interact with a number of proteins as they progress from their initial translation and nuclear translocation to heterodimerization with retinoid X receptors (RXRs), functional interactions with other transcription factors and the basic transcriptional apparatus, and eventually, degradation. To help elucidate the mechanisms that underlie the transcriptional effects and other potential functions of TRs, Lee et al. (1995) used the yeast interaction trap, a version of the yeast 2-hybrid system, to identify proteins that specifically interact with the ligand-binding domain of rat TR-beta (THRB; 190160). They isolated HeLa cell cDNAs encoding several different TR-interacting proteins (TRIPs), including TRIP15.
Some nuclear hormone receptors (NHRs) silence gene expression in the absence of hormone. Corepressors, which are bound to the silencing domain of NHRs and are involved in the repression of gene expression, dissociate upon hormone binding, leading to the binding of coactivators that mediate gene activation. Dressel et al. (1999) obtained a full-length HeLa cell cDNA encoding TRIP15, the human homolog of the Drosophila corepressor Alien. The predicted 305-amino acid TRIP15 protein, which is 90% identical to Drosophila Alien, contains an acidic region in the N terminus, a putative zinc finger in the C terminus, and a central hydrophobic core region flanked by 2 putative alpha-helical structures and a nuclear localization signal. Western blot analysis determined that TRIP15 is expressed as a 41-kD protein. Immunofluorescence microscopy demonstrated that TRIP15 localized in the nucleus.
Schaefer et al. (1999) obtained a mouse cDNA encoding Cops2, which is homologous to Drosophila Alien. The mouse gene encodes a larger protein than human TRIP15.
Lee et al. (1995) found that human TRIP15 interacted with rat Thrb only in the absence of thyroid hormone. In contrast, it interacted with RXR-alpha (RXRA; 180245) only in the presence of 9-cis-retinoic acid. TRIP15 did not interact with the glucocorticoid receptor (NR3C1; 138040) under any condition.
TR is a transcriptional silencer in the absence of hormone, as well as a hormone-dependent trans-activator, with its silencing domain localized in the C terminus. Yeast 2-hybrid, GST pull-down, and coimmunoprecipitation analyses showed that TRIP15 interacted with the C terminus of TR, but not with intact RAR (180240), only in the absence of hormone. Reporter assays indicated that TRIP15 increased receptor-mediated silencing and harbored an autonomous silencing function, which correlated with the ability of TRIP15 to interact with TR in both the hinge region and the C-terminal end of the TR silencing domain.
TRIP15, or SGN2, is part of a 450-kD signalosome complex that includes COPS3 (604665), COPS5 (604850), GPS1 (601934), and at least 4 other subunits. By autoradiographic analysis, Seeger et al. (1998) showed that the complex phosphorylates JUN (165160), IKBA (164008), and the C-terminal part of the p105 precursor of NFKB (164011). The 26S proteasome is not a phosphorylation target, although immunofluorescence microscopy demonstrated that the 450-kD complex has a cytosolic localization, concentrated around the nucleus.
SKP1 (601434)/CUL1 (603134)/F-box protein (see 605648) (SCF) complexes are ubiquitin ligases that regulate diverse cellular functions by ubiquitinating key regulatory proteins. SCF activity requires conjugation of NEDD8 (603171) to the cullin subunit, and the COP9 signalosome (CSN) inactivates SCF by catalyzing deconjugation of NEDD8. Min et al. (2005) found that CSN interacted with CUL1 irrespective of its neddylation state. Addition of CAND1 (607727), which bound only unneddylated CUL1, inhibited binding of CUL1 to CSN and enhanced the deneddylase activity of CSN in vitro. Coexpression of specific CSN subunits revealed that CSN1 (GPS1), CSN2, CSN4 (COPS4; 616008), and CSN5 provided the minimal core CUL1-binding unit.
Scherer et al. (2016) found that the conserved N-terminal acidic tail of CSN2 bound to the conserved C-terminal basic canyon of cullins (e.g., CUL4A; 603137), thereby mediating formation of CSN and cullin-RING ligase (CRL) complexes. Binding between CSN2 and cullins was enhanced by inositol hexakisphosphate (IP6) generated by inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPPK; 619043) in human cells.
Schaefer et al. (1999) determined that the mouse Trip15 gene contains 12 exons spanning 30 kb.
Scott (2000) mapped the TRIP15 gene to chromosome 15q21.2 based on sequence similarity between the TRIP15 sequence (GenBank AF120268) and the chromosome 15 clone RP11-325E5 (GenBank AC013452).
Schaefer et al. (1999) mapped the mouse Trip15 gene to the central part of chromosome 2.
Dressel, U., Thormeyer, D., Altincicek, B., Paululat, A., Eggert, M., Schneider, S., Tenbaum, S. P., Renkawitz, R., Baniahmad, A. Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily. Molec. Cell. Biol. 19: 3383-3394, 1999. [PubMed: 10207062] [Full Text: https://doi.org/10.1128/MCB.19.5.3383]
Lee, J. W., Choi, H.-S., Gyuris, J., Brent, R., Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Molec. Endocr. 9: 243-254, 1995. [PubMed: 7776974] [Full Text: https://doi.org/10.1210/mend.9.2.7776974]
Min, K.-W., Kwon, M.-J., Park, H.-S., Park, Y., Yoon, S. K., Yoon, J.-B. CAND1 enhances deneddylation of CUL1 by COP9 signalosome. Biochem. Biophys. Res. Commun. 334: 867-874, 2005. [PubMed: 16036220] [Full Text: https://doi.org/10.1016/j.bbrc.2005.06.188]
Schaefer, L., Beermann, M. L., Miller, J. B. Coding sequence, genomic organization, chromosomal localization, and expression pattern of the signalosome component Cops2: the mouse homologue of Drosophila alien. Genomics 56: 310-316, 1999. [PubMed: 10087198] [Full Text: https://doi.org/10.1006/geno.1998.5728]
Scherer, P. C., Ding, Y., Liu, Z., Xu, J., Mao, H.,, Barrow, J. C., Wei, N.,, Zheng, N., Snyder, S. H., Rao, F. Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc. Nat. Acad. Sci. 113: 3503-3508, 2016. [PubMed: 26976604] [Full Text: https://doi.org/10.1073/pnas.1525580113]
Scott, A. F. Personal Communication. Baltimore, Md. 11/8/2000.
Seeger, M., Kraft, R., Ferrell, K., Dawadschargal, B.-O., Dumdey, R., Schade, R., Gordon, C., Naumann, M., Dubiel, W. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J. 12: 469-478, 1998. [PubMed: 9535219]