ID GLI2_HUMAN Reviewed; 1586 AA. AC P10070; O60252; O60253; O60254; O60255; Q15590; Q15591; Q4JHT4; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 4. DT 04-NOV-2026, entry version 241. DE RecName: Full=Transcription activator GLI2 {ECO:0000305}; DE AltName: Full=GLI family zinc finger protein 2 {ECO:0000312|HGNC:HGNC:4318}; DE AltName: Full=Tax helper protein {ECO:0000303|PubMed:9557682}; DE Contains: DE RecName: Full=Transcription repressor GLI2R {ECO:0000305}; GN Name=GLI2 {ECO:0000303|PubMed:9557682, ECO:0000312|HGNC:HGNC:4318}; GN Synonyms=THP {ECO:0000303|PubMed:9557682}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), FUNCTION, DNA-BINDING, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND VARIANTS SER-1156 AND RP ASN-1306. RX PubMed=9557682; DOI=10.1128/jvi.72.5.3958-3964.1998; RA Tanimura A., Dan S., Yoshida M.; RT "Cloning of novel isoforms of the human Gli2 oncogene and their activities RT to enhance tax-dependent transcription of the human T-cell leukemia virus RT type 1 genome."; RL J. Virol. 72:3958-3964(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5), FUNCTION, AND INVOLVEMENT IN CJS. RX PubMed=15994174; DOI=10.1093/hmg/ddi222; RA Roessler E., Ermilov A.N., Grange D.K., Wang A., Grachtchouk M., RA Dlugosz A.A., Muenke M.; RT "A previously unidentified amino-terminal domain regulates transcriptional RT activity of wild-type and disease-associated human GLI2."; RL Hum. Mol. Genet. 14:2181-2188(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-857 (ISOFORMS 1; 2; 3 AND 4). RX PubMed=8350401; DOI=10.1128/jvi.67.9.5375-5382.1993; RA Tanimura A., Teshima H., Fujisawa J., Yoshida M.; RT "A new regulatory element that augments the Tax-dependent enhancer of human RT T-cell leukemia virus type 1 and cloning of cDNAs encoding its binding RT proteins."; RL J. Virol. 67:5375-5382(1993). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 456-560 (ISOFORMS 1; 2; 3 AND 4). RX PubMed=2850480; DOI=10.1128/mcb.8.8.3104-3113.1988; RA Ruppert J.M., Kinzler K.W., Wong A.J., Bigner S.H., Kao F.T., Law M.L., RA Seuanez H.N., O'Brien S.J., Vogelstein B.; RT "The GLI-Kruppel family of human genes."; RL Mol. Cell. Biol. 8:3104-3113(1988). RN [6] RP INTERACTION WITH STK36. RX PubMed=10806483; DOI=10.1038/35010610; RA Murone M., Luoh S.-L., Stone D., Li W., Gurney A., Armanini M., Grey C., RA Rosenthal A., de Sauvage F.J.; RT "Gli regulation by the opposing activities of fused and suppressor of RT fused."; RL Nat. Cell Biol. 2:310-312(2000). RN [7] RP INVOLVEMENT IN HPE9. RX PubMed=14581620; DOI=10.1073/pnas.2235734100; RA Roessler E., Du Y.-Z., Mullor J.L., Casas E., Allen W.P., RA Gillessen-Kaesbach G., Roeder E.R., Ming J.E., Ruiz i Altaba A., Muenke M.; RT "Loss-of-function mutations in the human GLI2 gene are associated with RT pituitary anomalies and holoprosencephaly-like features."; RL Proc. Natl. Acad. Sci. U.S.A. 100:13424-13429(2003). RN [8] RP FUNCTION, AND PHOSPHORYLATION AT SER-388 AND SER-1011. RX PubMed=18455992; DOI=10.1016/j.cell.2008.02.047; RA Varjosalo M., Bjorklund M., Cheng F., Syvanen H., Kivioja T., Kilpinen S., RA Sun Z., Kallioniemi O., Stunnenberg H.G., He W.W., Ojala P., Taipale J.; RT "Application of active and kinase-deficient kinome collection for RT identification of kinases regulating hedgehog signaling."; RL Cell 133:537-548(2008). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-234 AND SER-236, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [10] RP PHOSPHORYLATION, AND FUNCTION. RX PubMed=19878745; DOI=10.1016/j.yexcr.2009.10.018; RA Maloverjan A., Piirsoo M., Michelson P., Kogerman P., Osterlund T.; RT "Identification of a novel serine/threonine kinase ULK3 as a positive RT regulator of Hedgehog pathway."; RL Exp. Cell Res. 316:627-637(2010). RN [11] RP PHOSPHORYLATION. RX PubMed=20643644; DOI=10.1074/jbc.m110.133991; RA Maloverjan A., Piirsoo M., Kasak L., Peil L., Osterlund T., Kogerman P.; RT "Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog RT signaling pathway."; RL J. Biol. Chem. 285:30079-30090(2010). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=20154143; DOI=10.1128/mcb.01089-09; RA Wen X., Lai C.K., Evangelista M., Hongo J.A., de Sauvage F.J., Scales S.J.; RT "Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary RT cilia and subsequent degradation."; RL Mol. Cell. Biol. 30:1910-1922(2010). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-149; SER-234; SER-236 AND RP SER-242, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [14] RP ACETYLATION AT LYS-757. RX PubMed=23762415; DOI=10.1371/journal.pone.0065718; RA Coni S., Antonucci L., D'Amico D., Di Magno L., Infante P., De Smaele E., RA Giannini G., Di Marcotullio L., Screpanti I., Gulino A., Canettieri G.; RT "Gli2 acetylation at lysine 757 regulates hedgehog-dependent RT transcriptional output by preventing its promoter occupancy."; RL PLoS ONE 8:E65718-E65718(2013). RN [15] RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH SUFU. RX PubMed=24311597; DOI=10.1107/s0907444913028473; RA Cherry A.L., Finta C., Karlstrom M., Jin Q., Schwend T., Astorga-Wells J., RA Zubarev R.A., Del Campo M., Criswell A.R., de Sanctis D., Jovine L., RA Toftgard R.; RT "Structural basis of SUFU-GLI interaction in human Hedgehog signalling RT regulation."; RL Acta Crystallogr. D 69:2563-2579(2013). RN [16] RP INVOLVEMENT BY HPE9, INVOLVEMENT IN CJS, VARIANT CJS LEU-608, AND FUNCTION. RX PubMed=20685856; DOI=10.1210/jc.2010-1050; RA Franca M.M., Jorge A.A., Carvalho L.R., Costalonga E.F., Vasques G.A., RA Leite C.C., Mendonca B.B., Arnhold I.J.; RT "Novel heterozygous nonsense GLI2 mutations in patients with RT hypopituitarism and ectopic posterior pituitary lobe without RT holoprosencephaly."; RL J. Clin. Endocrinol. Metab. 95:E384-E391(2010). RN [17] RP FUNCTION, INTERACTION WITH FOXC1, AND SUBCELLULAR LOCATION. RX PubMed=26565916; DOI=10.1016/j.celrep.2015.09.063; RA Han B., Qu Y., Jin Y., Yu Y., Deng N., Wawrowsky K., Zhang X., Li N., RA Bose S., Wang Q., Sakkiah S., Abrol R., Jensen T.W., Berman B.P., RA Tanaka H., Johnson J., Gao B., Hao J., Liu Z., Buttyan R., Ray P.S., RA Hung M.C., Giuliano A.E., Cui X.; RT "FOXC1 activates smoothened-independent Hedgehog signaling in basal-like RT breast cancer."; RL Cell Rep. 13:1046-1058(2015). RN [18] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-50 (ISOFORMS 2 AND 4), AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [19] RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-252, AND RP MUTAGENESIS OF SER-252. RX PubMed=38968120; DOI=10.1073/pnas.2320070121; RA Yoshida S., Kawamura A., Aoki K., Wiriyasermkul P., Sugimoto S., RA Tomiyoshi J., Tajima A., Ishida Y., Katoh Y., Tsukada T., Tsuneoka Y., RA Yamada K., Nagamori S., Nakayama K., Yoshida K.; RT "Positive regulation of Hedgehog signaling via phosphorylation of GLI2/GLI3 RT by DYRK2 kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 121:e2320070121-e2320070121(2024). RN [20] RP VARIANTS HPE9 GLY-479; SER-932 AND LEU-1554, AND VARIANT ILE-1444. RX PubMed=17096318; DOI=10.1002/ajmg.a.31370; RA Rahimov F., Ribeiro L.A., de Miranda E., Richieri-Costa A., Murray J.C.; RT "GLI2 mutations in four Brazilian patients: how wide is the phenotypic RT spectrum?"; RL Am. J. Med. Genet. A 140:2571-2576(2006). RN [21] RP VARIANTS CJS PRO-516 AND 1444-MET-LEU-1445 DELINS ILE-PHE, CHARACTERIZATION RP OF VARIANTS CJS PRO-516 AND 1444-MET-LEU-1445 DELINS ILE-PHE, VARIANTS RP VAL-1352; ASN-1520 AND HIS-1543, AND CHARACTERIZATION OF VARIANTS VAL-1352; RP ASN-1520 AND HIS-1543. RX PubMed=23408573; DOI=10.1210/jc.2012-3224; RA Flemming G.M., Klammt J., Ambler G., Bao Y., Blum W.F., Cowell C., RA Donaghue K., Howard N., Kumar A., Sanchez J., Stobbe H., Pfaeffle R.W.; RT "Functional characterization of a heterozygous GLI2 missense mutation in RT patients with multiple pituitary hormone deficiency."; RL J. Clin. Endocrinol. Metab. 98:E567-E575(2013). RN [22] RP VARIANT ILE-1444. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). RN [23] RP VARIANTS VAL-1352 AND ASN-1520. RX PubMed=28973407; DOI=10.1093/hmg/ddx335; RA Palencia-Campos A., Ullah A., Nevado J., Yildirim R., Unal E., Ciorraga M., RA Barruz P., Chico L., Piceci-Sparascio F., Guida V., De Luca A., RA Kayserili H., Ullah I., Burmeister M., Lapunzina P., Ahmad W., RA Morales A.V., Ruiz-Perez V.L.; RT "GLI1 inactivation is associated with developmental phenotypes overlapping RT with Ellis-van Creveld syndrome."; RL Hum. Mol. Genet. 26:4556-4571(2017). CC -!- FUNCTION: Transcription factor that acts as a key effector of the CC smoothened signaling pathway, and which plays a role in skeleton CC development (PubMed:15994174, PubMed:18455992, PubMed:19878745, CC PubMed:20154143, PubMed:20685856, PubMed:24311597, PubMed:26565916, CC PubMed:9557682). Specifically binds to the minimal GLI-consensus CC sequence 5'-GACCACCCA-3' to activate or repress the expression of CC target genes (By similarity). Functions both as a transcriptional CC activator and repressor: the full-length GLI2 form (Transcription CC activator GLI2) acts as a transcription activator following smoothened CC activation, while the Transcription repressor GLI2R, which is generated CC in absence of smoothened, acts as a transcription repressor (By CC similarity). The transcriptional activator form constitutes the major CC form of GLI2 (By similarity). {ECO:0000250|UniProtKB:Q0VGT2, CC ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:18455992, CC ECO:0000269|PubMed:19878745, ECO:0000269|PubMed:20154143, CC ECO:0000269|PubMed:20685856, ECO:0000269|PubMed:24311597, CC ECO:0000269|PubMed:26565916, ECO:0000269|PubMed:9557682}. CC -!- FUNCTION: [Transcription activator GLI2]: Transcription factor, which CC activates expression of target genes in response to smoothened (SMO) CC activation (PubMed:18455992, PubMed:19878745, PubMed:24311597, CC PubMed:26565916, PubMed:9557682). Constitutes a major form of GLI2, CC while the transcription repressor form (GLI2R) plays a minor role (By CC similarity). {ECO:0000250|UniProtKB:Q0VGT2, CC ECO:0000269|PubMed:18455992, ECO:0000269|PubMed:19878745, CC ECO:0000269|PubMed:24311597, ECO:0000269|PubMed:26565916, CC ECO:0000269|PubMed:9557682}. CC -!- FUNCTION: [Transcription repressor GLI2R]: Transcription repressor, CC which inhibits expression of target genes in the absence of smoothened CC (SMO) signaling (By similarity). Generated by proteolytic processing of CC the full-length GLI2 form in the absence of hedgehog (DHH, IHH or SHH), CC when SMO transducer is inhibited (By similarity). Constitutes a minor CC form of GLI2, while the transcription activator GLI2 form plays a major CC role in smoothened signaling (By similarity). CC {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- FUNCTION: [Isoform 1]: Involved in the smoothened (SHH) signaling CC pathway. {ECO:0000269|PubMed:18455992}. CC -!- FUNCTION: [Isoform 2]: Involved in the smoothened (SHH) signaling CC pathway. {ECO:0000269|PubMed:18455992}. CC -!- FUNCTION: [Isoform 3]: Involved in the smoothened (SHH) signaling CC pathway. {ECO:0000269|PubMed:18455992}. CC -!- FUNCTION: [Isoform 4]: Involved in the smoothened (SHH) signaling CC pathway. {ECO:0000269|PubMed:18455992}. CC -!- FUNCTION: [Isoform 5]: Acts as a transcriptional repressor. CC {ECO:0000269|PubMed:15994174}. CC -!- FUNCTION: [Isoform 1]: (Microbial infection) Acts as a transcriptional CC activator in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a CC Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which CC is part of the Tax-responsive element (TRE-2S) regulatory element that CC augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682). CC {ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:9557682}. CC -!- FUNCTION: [Isoform 2]: (Microbial infection) Acts as a transcriptional CC activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a CC Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which CC is part of the Tax-responsive element (TRE-2S) regulatory element that CC augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682). CC {ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:9557682}. CC -!- FUNCTION: [Isoform 3]: (Microbial infection) Acts as a transcriptional CC activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a CC Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which CC is part of the Tax-responsive element (TRE-2S) regulatory element that CC augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682). CC {ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:9557682}. CC -!- FUNCTION: [Isoform 4]: (Microbial infection) Acts as a transcriptional CC activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a CC Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which CC is part of the Tax-responsive element (TRE-2S) regulatory element that CC augments the Tax-dependent enhancer of HTLV-1 (PubMed:9557682). CC {ECO:0000269|PubMed:15994174, ECO:0000269|PubMed:9557682}. CC -!- ACTIVITY REGULATION: Maintained in an inactive state by SUFU, which CC sequesters GLI2 in the cytoplasm (PubMed:24311597, PubMed:38968120). In CC presence of hedgehog (DHH, IHH or SHH), smoothened is activated, CC leading to phosphorylation by DYRK2 and dissociation from SUFU and CC translocation to the nucleus (PubMed:24311597, PubMed:38968120). CC Phosphorylated by ULK3 or STK36 in response to smoothened activation, CC promoting subsequent phosphorylation by CDK1 and dissociation from SUFU CC and translocation to the nucleus (By similarity). In absence of CC hedgehog, smoothened is inhibited, promoting processing of GLI2 into CC Transcription repressor GLI2R, which dissociates from SUFU and CC translocates to the nucleus (PubMed:38968120). CC {ECO:0000250|UniProtKB:Q0VGT2, ECO:0000269|PubMed:24311597, CC ECO:0000269|PubMed:38968120}. CC -!- SUBUNIT: Interacts with SUFU; sequestering GLI2 in the cytoplasm CC (PubMed:24311597, PubMed:38968120). Interaction with ZIC1 and ZIC2 (By CC similarity). Interacts with STK36; requires STK36 for full CC transcriptional activator activity (PubMed:10806483). Interacts with CC TMEM216; this interaction promotes nuclear localization of GLI2 (By CC similarity). Interacts (via C-terminal internal region) with FOXC1 (via CC N-terminus); this interaction is direct and increases GLI2 DNA-binding CC and transcriptional activity through a smoothened (SMO)-independent CC Hedgehog (Hh) signaling pathway (PubMed:26565916). CC {ECO:0000250|UniProtKB:Q0VGT2, ECO:0000269|PubMed:10806483, CC ECO:0000269|PubMed:24311597, ECO:0000269|PubMed:26565916, CC ECO:0000269|PubMed:38968120}. CC -!- INTERACTION: CC P10070; Q9Y297: BTRC; NbExp=4; IntAct=EBI-10821567, EBI-307461; CC P10070; P84022: SMAD3; NbExp=4; IntAct=EBI-10821567, EBI-347161; CC P10070; Q99816: TSG101; NbExp=2; IntAct=EBI-10821567, EBI-346882; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:10806483, CC ECO:0000269|PubMed:26565916}. Cytoplasm {ECO:0000250|UniProtKB:Q0VGT2}. CC Cell projection, cilium {ECO:0000269|PubMed:20154143}. Note=Full-length CC GLI2 is sequestered in the cytoplasm by SUFU in absence of smoothened CC signaling. {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- SUBCELLULAR LOCATION: [Transcription activator GLI2]: Nucleus CC {ECO:0000269|PubMed:10806483, ECO:0000269|PubMed:38968120}. Cytoplasm CC {ECO:0000269|PubMed:38968120}. Cell projection, cilium CC {ECO:0000269|PubMed:20154143}. Note=Sequestered in the cytoplasm by CC SUFU in absence of smoothened signaling (PubMed:38968120). Accumulates CC in primary cilia following smoothened activation (PubMed:20154143). It CC then translocates to the nucleus, where is activates transcription of CC target genes (PubMed:38968120). TMEM216 promotes its nuclear CC localization (By similarity). STK36 promotes translocation to the CC nucleus (PubMed:10806483). {ECO:0000250|UniProtKB:Q0VGT2, CC ECO:0000269|PubMed:10806483, ECO:0000269|PubMed:20154143, CC ECO:0000269|PubMed:38968120}. CC -!- SUBCELLULAR LOCATION: [Transcription repressor GLI2R]: Nucleus CC {ECO:0000250|UniProtKB:Q0VGT2}. Note=Following generation by CC proteolytic processing in absence of smoothened, translocates to the CC nucleus, where is represses transcription of target genes. CC {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Nucleus CC {ECO:0000269|PubMed:9557682}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus CC {ECO:0000269|PubMed:9557682}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=5; Synonyms=GLI2 {ECO:0000303|PubMed:15994174}; CC IsoId=P10070-5; Sequence=Displayed; CC Name=1; Synonyms=Alpha, GLI2star, GLI2deltaN CC {ECO:0000303|PubMed:15994174, ECO:0000303|PubMed:9557682}; CC IsoId=P10070-1; Sequence=VSP_035708; CC Name=2; Synonyms=Beta {ECO:0000303|PubMed:9557682}; CC IsoId=P10070-2; Sequence=VSP_035708, VSP_006877; CC Name=3; Synonyms=Gamma {ECO:0000303|PubMed:9557682}; CC IsoId=P10070-3; Sequence=VSP_035708, VSP_006878, VSP_006879; CC Name=4; Synonyms=Delta {ECO:0000303|PubMed:9557682}; CC IsoId=P10070-4; Sequence=VSP_035708, VSP_006877, VSP_006878, CC VSP_006879; CC -!- TISSUE SPECIFICITY: Expressed in breast cancers (at protein level) CC (PubMed:26565916). Isoform 1 and isoform 4 are expressed in HTLV-1- CC infected T-cell lines (at protein level) (PubMed:9557682). Isoform 1 CC and isoform 2 are strongly expressed in HTLV-1-infected T-cell lines CC (PubMed:9557682). Isoform 3 and isoform 4 are weakly expressed in HTLV- CC 1-infected T-cell lines (PubMed:9557682). {ECO:0000269|PubMed:26565916, CC ECO:0000269|PubMed:9557682}. CC -!- DOMAIN: The N-terminal domain confers transcriptional repressor CC activity, while the C-terminal domain mediates transcriptional CC activation. {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- PTM: Acetylation at Lys-757 inhibits Hh target gene expression, CC probably by impeding entry into chromatin thus preventing promoter CC occupancy. {ECO:0000269|PubMed:23762415}. CC -!- PTM: In absence of smoothened, phosphorylated on multiple sites by CC protein kinase A (PKA), priming further phosphorylation by CK1 and CC GSK3B: phosphorylation promotes ubiquitination by the SCF(BTRC) complex CC and partial proteolysis to generate the Transcription repressor GLI2R CC form (By similarity). Phosphorylated by DYRK2; this inhibits GLI2 CC transcription factor activity and promotes proteasomal degradation of CC GLI2 (PubMed:18455992). {ECO:0000250|UniProtKB:Q0VGT2, CC ECO:0000269|PubMed:18455992}. CC -!- PTM: [Transcription activator GLI2]: Phosphorylation at Ser-252 by CC DYRK2 in response to smoothened activation, promotes GLI2 dissociation CC from SUFU inhibitor and translocation to the nucleus (PubMed:38968120). CC Phosphorylated by ULK3 (PubMed:19878745). Phosphorylation by ULK3 or CC STK36 in response to smoothened activation promotes subsequent CC phosphorylation by CDK1 and GLI2 dissociation from SUFU inhibitor, CC followed by translocation to the nucleus (By similarity). CC {ECO:0000250|UniProtKB:Q0VGT2, ECO:0000269|PubMed:19878745, CC ECO:0000269|PubMed:38968120}. CC -!- PTM: In absence of smoothened signaling, ubiquitinated by the SCF(BTRC) CC complex following phosphorylation by PKA and GSK3B, promoting mainly CC degradation, as well as a small fraction of the Transcription repressor CC GLI2R form. {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- PTM: [Transcription repressor GLI2R]: Generated from the full-length CC GLI2 protein through proteolytic processing (By similarity). This CC process requires PKA-primed phosphorylation of GLI2, ubiquitination by CC the SCF(BTRC) complex and limited proteolysis (By similarity). In CC absence of smoothened signaling, only a small fraction of full-length CC GLI2 is converted into Transcription repressor GLI2R form, the main CC fraction of the protein beeing degraded (By similarity). CC {ECO:0000250|UniProtKB:Q0VGT2}. CC -!- DISEASE: Holoprosencephaly 9 (HPE9) [MIM:610829]: A form of CC holoprosencephaly, a structural anomaly of the brain in which the CC developing forebrain fails to correctly separate into right and left CC hemispheres. It is a genetically and clinically heterogeneous disorder CC with a wide spectrum of severity, ranging from alobar holoprosencephaly CC with severe facial abnormalities, such as cyclopia and proboscis, to CC mild forms that include lobar or microform holoprosencephaly, without CC cerebral malformations and with mild craniofacial defects. HPE9 is CC characterized by defective anterior pituitary formation and pan- CC hypopituitarism, with or without overt forebrain cleavage CC abnormalities, and holoprosencephaly-like midfacial hypoplasia. HPE9 CC inheritance is autosomal dominant. {ECO:0000269|PubMed:14581620, CC ECO:0000269|PubMed:17096318, ECO:0000269|PubMed:20685856}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Culler-Jones syndrome (CJS) [MIM:615849]: An autosomal CC dominant disorder with incomplete penetrance and variable expressivity, CC characterized by pituitary abnormalities including ectopic or non- CC visible posterior pituitary lobe, growth hormone deficiency, combined CC pituitary hormone deficiency, and, in some patients, additional CC features such as postaxial polydactyly, midline facial defects, and CC developmental delay. {ECO:0000269|PubMed:15994174, CC ECO:0000269|PubMed:20685856, ECO:0000269|PubMed:23408573, CC ECO:0000269|PubMed:28973407}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the GLI C2H2-type zinc-finger protein family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA03568.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA03569.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA25665.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA25667.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB007295; BAA25665.1; ALT_FRAME; mRNA. DR EMBL; AB007296; BAA25666.1; -; mRNA. DR EMBL; AB007297; BAA25667.1; ALT_FRAME; mRNA. DR EMBL; AB007298; BAA25668.1; -; mRNA. DR EMBL; DQ086814; AAY87165.1; -; mRNA. DR EMBL; AC016764; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC017033; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; D14827; BAA03568.1; ALT_FRAME; mRNA. DR EMBL; D14828; BAA03569.1; ALT_FRAME; mRNA. DR EMBL; M20672; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; M20673; AAA35898.1; -; Genomic_DNA. DR CCDS; CCDS33283.1; -. [P10070-5] DR PIR; A31201; A31201. DR PIR; A40679; A40679. DR PIR; B40679; B40679. DR RefSeq; NP_001358200.1; NM_001371271.1. [P10070-5] DR RefSeq; NP_001432722.1; NM_001445793.1. [P10070-5] DR RefSeq; NP_005261.2; NM_005270.5. [P10070-5] DR AlphaFoldDB; P10070; -. DR SMR; P10070; -. DR BioGRID; 108998; 63. DR ComplexPortal; CPX-148; GLI2-SUFU complex. DR FunCoup; P10070; 1329. DR IntAct; P10070; 48. DR NDEx; IQUERY-CP-GLI2; 16 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000390436; -. DR BindingDB; P10070; -. DR ChEMBL; CHEMBL5119; -. DR GlyCosmos; P10070; 11 sites, 2 glycans. DR GlyGen; P10070; 11 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (5 sites). DR iPTMnet; P10070; -. DR PhosphoSitePlus; P10070; -. DR BioMuta; GLI2; -. DR DMDM; 215274258; -. DR jPOST; P10070; -. DR MassIVE; P10070; -. DR PaxDb; 9606-ENSP00000390436; -. DR PeptideAtlas; P10070; -. DR ProteomicsDB; 52552; -. [P10070-5] DR ProteomicsDB; 52553; -. [P10070-1] DR ProteomicsDB; 52554; -. [P10070-2] DR ProteomicsDB; 52555; -. [P10070-3] DR ProteomicsDB; 52556; -. [P10070-4] DR Pumba; P10070; -. DR Antibodypedia; 3768; 423 antibodies from 41 providers. DR DNASU; 2736; -. DR Ensembl; ENST00000452319.6; ENSP00000390436.1; ENSG00000074047.23. [P10070-5] DR GeneID; 2736; -. DR KEGG; hsa:2736; -. DR UCSC; uc010flp.4; human. [P10070-5] DR AGR; HGNC:4318; -. DR ClinPGx; PA28721; -. DR CTD; 2736; -. DR DisGeNET; 2736; -. DR GeneCards; GLI2; -. DR GeneReviews; GLI2; -. DR HGNC; HGNC:4318; GLI2. DR HPA; ENSG00000074047; Tissue enhanced (ovary). DR MalaCards; GLI2; -. DR MIM; 165230; gene. DR MIM; 610829; phenotype. DR MIM; 615849; phenotype. DR OpenTargets; ENSG00000074047; -. DR Orphanet; 93925; Alobar holoprosencephaly. DR Orphanet; 95494; Combined pituitary hormone deficiencies, genetic forms. DR Orphanet; 93924; Lobar holoprosencephaly. DR Orphanet; 280200; Microform holoprosencephaly. DR Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly. DR Orphanet; 420584; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome. DR Orphanet; 220386; Semilobar holoprosencephaly. DR Orphanet; 280195; Septopreoptic holoprosencephaly. DR VEuPathDB; HostDB:ENSG00000074047; -. DR eggNOG; KOG1721; Eukaryota. DR GeneTree; ENSGT00940000159213; -. DR HOGENOM; CLU_003666_2_0_1; -. DR InParanoid; P10070; -. DR OMA; AADHQTM; -. DR OrthoDB; 3214149at2759; -. DR PAN-GO; P10070; 5 GO annotations based on evolutionary models. DR PhylomeDB; P10070; -. DR PathwayCommons; P10070; -. DR Reactome; R-HSA-5610783; Degradation of GLI2 by the proteasome. DR Reactome; R-HSA-5610787; Hedgehog 'off' state. DR Reactome; R-HSA-5632684; Hedgehog 'on' state. DR Reactome; R-HSA-5635851; GLI proteins bind promoters of Hh responsive genes to promote transcription. DR Reactome; R-HSA-8941284; RUNX2 regulates chondrocyte maturation. DR SignaLink; P10070; -. DR SIGNOR; P10070; -. DR Agora; ENSG00000074047; -. DR BioGRID-ORCS; 2736; 16 hits in 1175 CRISPR screens. DR GeneWiki; GLI2; -. DR GenomeRNAi; 2736; -. DR Pharos; P10070; Tchem. DR PRO; PR:P10070; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P10070; protein. DR Bgee; ENSG00000074047; Expressed in tibia and 154 other cell types or tissues. DR ExpressionAtlas; P10070; baseline and differential. DR GO; GO:0005813; C:centrosome; IDA:HPA. DR GO; GO:0036064; C:ciliary basal body; IDA:HPA. DR GO; GO:0097546; C:ciliary base; TAS:Reactome. DR GO; GO:0097542; C:ciliary tip; TAS:Reactome. DR GO; GO:0005929; C:cilium; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0097730; C:non-motile cilium; IDA:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:UniProt. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central. DR GO; GO:1990841; F:promoter-specific chromatin binding; IDA:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB. DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; ISS:UniProtKB. DR GO; GO:0098586; P:cellular response to virus; IDA:UniProtKB. DR GO; GO:0021696; P:cerebellar cortex morphogenesis; ISS:UniProtKB. DR GO; GO:0048589; P:developmental growth; ISS:UniProtKB. DR GO; GO:0048566; P:embryonic digestive tract development; ISS:UniProtKB. DR GO; GO:0009913; P:epidermal cell differentiation; IDA:UniProtKB. DR GO; GO:0021508; P:floor plate formation; ISS:UniProtKB. DR GO; GO:0031069; P:hair follicle morphogenesis; IMP:UniProtKB. DR GO; GO:0007507; P:heart development; ISS:UniProtKB. DR GO; GO:0030902; P:hindbrain development; ISS:UniProtKB. DR GO; GO:0007442; P:hindgut morphogenesis; ISS:UniProtKB. DR GO; GO:0001822; P:kidney development; ISS:UniProtKB. DR GO; GO:0030324; P:lung development; ISS:UniProtKB. DR GO; GO:0030879; P:mammary gland development; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0048666; P:neuron development; ISS:UniProtKB. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; ISS:UniProtKB. DR GO; GO:0002076; P:osteoblast development; ISS:UniProtKB. DR GO; GO:0001649; P:osteoblast differentiation; IDA:UniProtKB. DR GO; GO:0007389; P:pattern specification process; ISS:UniProtKB. DR GO; GO:0021983; P:pituitary gland development; ISS:UniProtKB. DR GO; GO:0045740; P:positive regulation of DNA replication; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; ISS:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0009954; P:proximal/distal pattern formation; ISS:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0001501; P:skeletal system development; ISS:UniProtKB. DR GO; GO:0007224; P:smoothened signaling pathway; IDA:UniProtKB. DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; ISS:UniProtKB. DR GO; GO:0021965; P:spinal cord ventral commissure morphogenesis; ISS:UniProtKB. DR GO; GO:0035295; P:tube development; ISS:UniProtKB. DR GO; GO:0007418; P:ventral midline development; ISS:UniProtKB. DR GO; GO:0021517; P:ventral spinal cord development; ISS:UniProtKB. DR FunFam; 3.30.160.60:FF:000019; GLI family zinc finger 3; 1. DR FunFam; 3.30.160.60:FF:000031; GLI family zinc finger 3; 1. DR FunFam; 3.30.160.60:FF:000036; GLI family zinc finger 3; 1. DR FunFam; 3.30.160.60:FF:000048; GLI family zinc finger 3; 1. DR FunFam; 3.30.160.60:FF:000068; GLI family zinc finger 3; 1. DR Gene3D; 3.30.160.60; Classic Zinc Finger; 5. DR InterPro; IPR043359; GLI-like. DR InterPro; IPR013087; Zf-C2H2_type. DR InterPro; IPR056436; Znf-C2H2_ZIC1-5/GLI1-3-like. DR InterPro; IPR036236; Znf_C2H2_sf. DR PANTHER; PTHR45718; TRANSCRIPTIONAL ACTIVATOR CUBITUS INTERRUPTUS; 1. DR PANTHER; PTHR45718:SF6; ZINC FINGER PROTEIN GLI2; 1. DR Pfam; PF00096; zf-C2H2; 2. DR Pfam; PF23561; zf-C2H2_15; 1. DR SMART; SM00355; ZnF_C2H2; 5. DR SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 4. DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 4. PE 1: Evidence at protein level; KW Acetylation; Activator; Alternative splicing; Cell projection; Cilium; KW Cytoplasm; Developmental protein; Disease variant; DNA-binding; KW Holoprosencephaly; Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Repeat; Repressor; KW Transcription; Transcription regulation; Ubl conjugation; Zinc; KW Zinc-finger. FT CHAIN 1..1586 FT /note="Transcription activator GLI2" FT /id="PRO_0000354050" FT CHAIN 1..? FT /note="Transcription repressor GLI2R" FT /id="PRO_0000463997" FT ZN_FING 437..464 FT /note="C2H2-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 475..497 FT /note="C2H2-type 2; degenerate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 503..527 FT /note="C2H2-type 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 533..558 FT /note="C2H2-type 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT ZN_FING 564..589 FT /note="C2H2-type 5" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042" FT REGION 1..328 FT /note="Repressor domain" FT /evidence="ECO:0000250|UniProtKB:P10071" FT REGION 1..22 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 342..389 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 577..636 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 650..716 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 742..879 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 783..1102 FT /note="Activator domain" FT /evidence="ECO:0000250|UniProtKB:P10071" FT REGION 925..1030 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1182..1215 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1421..1441 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1469..1498 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..10 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 342..367 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 589..605 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 654..674 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 791..802 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 809..824 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 947..961 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 968..977 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1469..1485 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 149 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 234 FT /note="Phosphoserine; by STK36 and ULK3" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231" FT MOD_RES 236 FT /note="Phosphoserine; by ULK3" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231" FT MOD_RES 242 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 252 FT /note="Phosphoserine; by DYRK2" FT /evidence="ECO:0000269|PubMed:38968120" FT MOD_RES 388 FT /note="Phosphoserine; by DYRK2" FT /evidence="ECO:0000269|PubMed:18455992" FT MOD_RES 725 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 757 FT /note="N6-acetyllysine; by EP300" FT /evidence="ECO:0000269|PubMed:23762415" FT MOD_RES 808 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 811 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 820 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 824 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 827 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 832 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 836 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 839 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 863 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 867 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 870 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000250|UniProtKB:Q0VGT2" FT MOD_RES 1011 FT /note="Phosphoserine; by DYRK2" FT /evidence="ECO:0000269|PubMed:18455992" FT VAR_SEQ 1..328 FT /note="Missing (in isoform 1, isoform 2, isoform 3 and FT isoform 4)" FT /evidence="ECO:0000303|PubMed:8350401, FT ECO:0000303|PubMed:9557682" FT /id="VSP_035708" FT VAR_SEQ 394..410 FT /note="Missing (in isoform 2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:8350401, FT ECO:0000303|PubMed:9557682" FT /id="VSP_006877" FT VAR_SEQ 1149..1157 FT /note="VSSGTVDAL -> ASATWLSGT (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:8350401, FT ECO:0000303|PubMed:9557682" FT /id="VSP_006878" FT VAR_SEQ 1158..1586 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:8350401, FT ECO:0000303|PubMed:9557682" FT /id="VSP_006879" FT VARIANT 449 FT /note="D -> H (in dbSNP:rs13427953)" FT /id="VAR_047303" FT VARIANT 479 FT /note="R -> G (in HPE9; uncertain significance; FT dbSNP:rs121917708)" FT /evidence="ECO:0000269|PubMed:17096318" FT /id="VAR_032975" FT VARIANT 516 FT /note="R -> P (in CJS; loss of DNA-binding; loss of FT transcription factor activity)" FT /evidence="ECO:0000269|PubMed:23408573" FT /id="VAR_075214" FT VARIANT 579 FT /note="S -> I (in dbSNP:rs12618388)" FT /id="VAR_047304" FT VARIANT 608 FT /note="P -> L (in CJS; dbSNP:rs149800897)" FT /evidence="ECO:0000269|PubMed:20685856" FT /id="VAR_071700" FT VARIANT 625 FT /note="P -> S (in dbSNP:rs3099537)" FT /id="VAR_047305" FT VARIANT 932 FT /note="P -> S (in HPE9; uncertain significance; FT dbSNP:rs1272759660)" FT /evidence="ECO:0000269|PubMed:17096318" FT /id="VAR_032976" FT VARIANT 1156 FT /note="A -> S (in dbSNP:rs3738880)" FT /evidence="ECO:0000269|PubMed:9557682" FT /id="VAR_047306" FT VARIANT 1306 FT /note="D -> N (in dbSNP:rs12711538)" FT /evidence="ECO:0000269|PubMed:9557682" FT /id="VAR_047307" FT VARIANT 1352 FT /note="M -> V (found in Culler-Jones syndrome; when FT associated in cis with N-1520; decreased transcription FT factor activity when associated in cis with N-1520; FT dbSNP:rs149140724)" FT /evidence="ECO:0000269|PubMed:23408573, FT ECO:0000269|PubMed:28973407" FT /id="VAR_075215" FT VARIANT 1444..1445 FT /note="ML -> IF (in CJS; uncertain significance; decreased FT transcription factor activity)" FT /evidence="ECO:0000269|PubMed:23408573" FT /id="VAR_075216" FT VARIANT 1444 FT /note="M -> I (in dbSNP:rs146467786)" FT /evidence="ECO:0000269|PubMed:17096318, FT ECO:0000269|PubMed:27535533" FT /id="VAR_032977" FT VARIANT 1520 FT /note="D -> N (found in Culler-Jones syndrome; when FT associated in cis with V-1352 in Culler-Jones syndrome; FT decreased transcription factor activity when associated in FT cis with V-1352; dbSNP:rs114814747)" FT /evidence="ECO:0000269|PubMed:23408573, FT ECO:0000269|PubMed:28973407" FT /id="VAR_075217" FT VARIANT 1543 FT /note="R -> H (no effect on transcription factor activity; FT dbSNP:rs138987487)" FT /evidence="ECO:0000269|PubMed:23408573" FT /id="VAR_075218" FT VARIANT 1554 FT /note="P -> L (in HPE9; uncertain significance; FT dbSNP:rs767802807)" FT /evidence="ECO:0000269|PubMed:17096318" FT /id="VAR_032978" FT MUTAGEN 252 FT /note="S->A: Abolished phosphorylation by DYRK2, leading to FT decreased dossiciation from SUFU." FT /evidence="ECO:0000269|PubMed:38968120" FT CONFLICT 456 FT /note="H -> Q (in Ref. 5; M20672)" FT /evidence="ECO:0000305" FT CONFLICT 718..719 FT /note="QL -> HV (in Ref. 4; BAA03568/BAA03569)" FT /evidence="ECO:0000305" FT CONFLICT 923..925 FT /note="PER -> AEG (in Ref. 1; FT BAA25665/BAA25667/BAA25666/BAA25668)" FT /evidence="ECO:0000305" FT CONFLICT 966 FT /note="A -> T (in Ref. 1; FT BAA25665/BAA25667/BAA25666/BAA25668)" FT /evidence="ECO:0000305" FT CROSSLNK P10070-2:50 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK P10070-4:50 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" SQ SEQUENCE 1586 AA; 167783 MW; 86556112E13DE106 CRC64; METSASATAS EKQEAKSGIL EAAGFPDPGK KASPLVVAAA AAAAVAAQGV PQHLLPPFHA PLPIDMRHQE GRYHYEPHSV HGVHGPPALS GSPVISDISL IRLSPHPAGP GESPFNAPHP YVNPHMEHYL RSVHSSPTLS MISAARGLSP ADVAQEHLKE RGLFGLPAPG TTPSDYYHQM TLVAGHPAPY GDLLMQSGGA ASAPHLHDYL NPVDVSRFSS PRVTPRLSRK RALSISPLSD ASLDLQRMIR TSPNSLVAYI NNSRSSSAAS GSYGHLSAGA LSPAFTFPHP INPVAYQQIL SQQRGLGSAF GHTPPLIQPS PTFLAQQPMA LTSINATPTQ LSSSSNCLSD TNQNKQSSES AVSSTVNPVA IHKRSKVKTE PEGLRPASPL ALTQGQVSGH GSCGCALPLS QEQLADLKED LDRDDCKQEA EVVIYETNCH WEDCTKEYDT QEQLVHHINN EHIHGEKKEF VCRWQACTRE QKPFKAQYML VVHMRRHTGE KPHKCTFEGC SKAYSRLENL KTHLRSHTGE KPYVCEHEGC NKAFSNASDR AKHQNRTHSN EKPYICKIPG CTKRYTDPSS LRKHVKTVHG PDAHVTKKQR NDVHLRTPLL KENGDSEAGT EPGGPESTEA SSTSQAVEDC LHVRAIKTES SGLCQSSPGA QSSCSSEPSP LGSAPNNDSG VEMPGTGPGS LGDLTALDDT PPGADTSALA APSAGGLQLR KHMTTMHRFE QLKKEKLKSL KDSCSWAGPT PHTRNTKLPP LPGSGSILEN FSGSGGGGPA GLLPNPRLSE LSASEVTMLS QLQERRDSST STVSSAYTVS RRSSGISPYF SSRRSSEASP LGAGRPHNAS SADSYDPIST DASRRSSEAS QCSGGSGLLN LTPAQQYSLR AKYAAATGGP PPTPLPGLER MSLRTRLALL DAPERTLPAG CPRPLGPRRG SDGPTYGHGH AGAAPAFPHE APGGGARRAS DPVRRPDALS LPRVQRFHST HNVNPGPLPP CADRRGLRLQ SHPSTDGGLA RGAYSPRPPS ISENVAMEAV AAGVDGAGPE ADLGLPEDDL VLPDDVVQYI KAHASGALDE GTGQVYPTES TGFSDNPRLP SPGLHGQRRM VAADSNVGPS APMLGGCQLG FGAPSSLNKN NMPVQWNEVS SGTVDALASQ VKPPPFPQGN LAVVQQKPAF GQYPGYSPQG LQASPGGLDS TQPHLQPRSG APSQGIPRVN YMQQLRQPVA GSQCPGMTTT MSPHACYGQV HPQLSPSTIS GALNQFPQSC SNMPAKPGHL GHPQQTEVAP DPTTMGNRHR ELGVPDSALA GVPPPHPVQS YPQQSHHLAA SMSQEGYHQV PSLLPARQPG FMEPQTGPMG VATAGFGLVQ PRPPLEPSPT GRHRGVRAVQ QQLAYARATG HAMAAMPSSQ ETAEAVPKGA MGNMGSVPPQ PPPQDAGGAP DHSMLYYYGQ IHMYEQDGGL ENLGSCQVMR SQPPQPQACQ DSIQPQPLPS PGVNQVSSTV DSQLLEAPQI DFDAIMDDGD HSSLFSGALS PSLLHSLSQN SSRLTTPRNS LTLPSIPAGI SNMAVGDMSS MLTSLAEESK FLNMMT //