Human Gene GLI3 (ENST00000395925.8) from GENCODE V43
Description: Homo sapiens GLI family zinc finger 3 (GLI3), mRNA. (from RefSeq NM_000168) RefSeq Summary (NM_000168): This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Gencode Transcript: ENST00000395925.8 Gencode Gene: ENSG00000106571.15 Transcript (Including UTRs) Position: hg38 chr7:41,960,949-42,237,209 Size: 276,261 Total Exon Count: 15 Strand: - Coding Region Position: hg38 chr7:41,964,330-42,223,253 Size: 258,924 Coding Exon Count: 14
ID:GLI3_HUMAN DESCRIPTION: RecName: Full=Transcriptional activator GLI3; AltName: Full=GLI3 form of 190 kDa; Short=GLI3-190; AltName: Full=GLI3 full length protein; Short=GLI3FL; Contains: RecName: Full=Transcriptional repressor GLI3R; AltName: Full=GLI3 C-terminally truncated form; AltName: Full=GLI3 form of 83 kDa; Short=GLI3-83; FUNCTION: Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. SUBUNIT: The full-length GLI3 form (GLI3FL) interacts with SUFU and this interaction regulates the formation of either repressor or activator forms of GLI3. Its association with SUFU is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A (By similarity). Interacts with KIF7. The activator form of GLI3 (GLI3A) but not the repressor form (GLI3R) can interact with TRPS1. The phosphorylated form interacts with BTRC. Interacts with ZIC1. Interacts with ZIC3 (via C2H2-type domains 3, 4 and 5); the interaction enhances its transcriptional activity. INTERACTION: P46684:Zic1 (xeno); NbExp=2; IntAct=EBI-308055, EBI-308006; Q62520:Zic2 (xeno); NbExp=2; IntAct=EBI-308055, EBI-308076; SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cell projection, cilium. Note=GLI3FL is localized predominantly in the cytoplasm while GLI3R resides mainly in the nucleus. Ciliary accumulation requires the presence of KIF7 and SMO. Translocation to the nucleus is promoted by interaction with ZIC1. TISSUE SPECIFICITY: Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium. PTM: Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylation is essential for its proteolytic processing. PTM: Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3- 190) through proteolytic processing. This process requires PKA- primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3. DISEASE: Defects in GLI3 are the cause of Greig cephalo-poly- syndactyly syndrome (GCPS) [MIM:175700]. GCPS is an autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism. DISEASE: Defects in GLI3 are a cause of Pallister-Hall syndrome (PHS) [MIM:146510]. PHS is characterized by a wide range of clinical manifestations. It mainly associates central or postaxial polydactyly, syndactyly, and hypothalamic hamartoma. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. It is an autosomal dominant disorder. DISEASE: Defects in GLI3 are a cause of polydactyly postaxial type A1 (PAPA1) [MIM:174200]. A trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional. DISEASE: Defects in GLI3 are a cause of polydactyly postaxial type B polydactyly (PAPB) [MIM:174200]. A trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is not well formed and is frequently in the form of a skin. DISEASE: Defects in GLI3 are a cause of polydactyly preaxial type 4 (POP4) [MIM:174700]. Polydactyly preaxial type 4 (i.e. polydactyly on the radial/tibial side of the hand/foot) covers a heterogeneous group of entities. In preaxial polydactyly type IV, the thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. SIMILARITY: Belongs to the GLI C2H2-type zinc-finger protein family. SIMILARITY: Contains 5 C2H2-type zinc fingers. SEQUENCE CAUTION: Sequence=AAA52564.1; Type=Frameshift; Positions=1549; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GLI3";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P10071
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
M57609 - Human DNA-binding protein (GLI3) mRNA, complete cds. AK299299 - Homo sapiens cDNA FLJ50841 complete cds, highly similar to Zinc finger protein GLI3. BC117168 - Homo sapiens GLI family zinc finger 3, mRNA (cDNA clone MGC:150777 IMAGE:40125719), complete cds. BC113616 - Homo sapiens GLI family zinc finger 3, mRNA (cDNA clone MGC:142176 IMAGE:8322668), complete cds. AB489183 - Synthetic construct DNA, clone: pF1KE1055, Homo sapiens GLI3 gene for GLI-Kruppel family member GLI3, without stop codon, in Flexi system. AK308429 - Homo sapiens cDNA, FLJ98377. BC032660 - Homo sapiens cDNA clone IMAGE:5532335, partial cds.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04340 - Hedgehog signaling pathway hsa05200 - Pathways in cancer hsa05217 - Basal cell carcinoma
BioCarta from NCI Cancer Genome Anatomy Project h_shhPathway - Sonic Hedgehog (Shh) Pathway