LIG_SUFU_1

The hedgehog (Hh) signalling pathway regulates cell proliferation and tissue patterning during metazoan embryonic development. As proper regulation of Hh pathway is required for the correct formation of organs, defective Hh signalling results in severe developmental defects. For instance, in limbs, the Hh pathway is involved in digit development, and excess signalling leads to the formation of extra digits. In addition, aberrant activation of Hh signalling has been associated with various types of cancer, including basal cell carcinoma and medulloblastoma. The Hh pathway is conserved in vertebrates and invertebrates. However, while primary cilia do not exist in flies, Hh signalling in mammals is coupled to this organelle, which acts as a signalling centre where most of the critical components of the Hh pathway are localised and regulated (Haycraft,2005; Goetz,2010).
The Hh pathway was initially identified in Drosophila melanogaster with the discovery of a gene (hh, encoding Protein hedgehog) involved in embryonic segment polarity (Nusslein-Volhard,1981; Varjosalo,2008). Hedgehog signalling is initiated by binding of the Hh ligand to its receptor Patched (Ptc) and ultimately results in the activation of several GLI C2H2-type zinc-finger protein family members (the Gli1, Gli2 and Gli3 proteins in vertebrates and the Ci protein in Drosophila melanogaster). These transcription factors can then activate the expression of specific target genes that are responsible for cell development and tissue maintenance (Varjosalo,2008). While Gli1 mainly acts as a transcriptional activator, Gli2 and Gli3 can act both as activators and repressors depending on specific post-translational modifications. For instance, in the absence of Hh signalling, the transcription factor Gli3 functions as a repressor that prevents the expression of Hh target genes, but upon Hh pathway activation differentially phosphorylated Gli3 promotes transcription (Humke,2010).
The transcriptional activity of these GLI proteins is inhibited by the SUFU (Suppressor of fused homolog) protein, which thus negatively regulates Hh signalling (Ding,2000). In addition to Gli proteins, the GLI protein family also includes several other zinc-finger proteins such as the Gli-similar (Glis) and ZIC proteins. SUFU was found to also interact with and regulate Glis transcription factors. For instance, binding of SUFU to Glis3 was shown to inhibit activation of the insulin promoter by Glis3 but also stabilise Glis3 by preventing its poly-ubiquitylation-dependent proteasomal degradation (ZeRuth,2011). The interaction between SUFU and the GLI proteins it regulates is mediated by a conserved motif in these transcription factors, however, not all members of this family seem to contain a functional SUFU-binding motif. Also, while the Drosophila melanogaster family member protein Opa (P39768) contains a peptide sequence similar to the SUFU-binding motif in the Drosophila melanogaster Gli homologue Ci (P19538), the vertebrate Opa-homologous ZIC proteins do not have a sequence resembling this motif and an interaction between Opa and Sufu has not yet been characterised. In addition, several other zinc finger proteins that do not belong to the GLI family (Q8WXB4 and Q96H86) contain a similar sequence, however these peptides are not located in a disordered region and not well conserved, and thus likely not functional.