Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling

Abstract

Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling in vertebrates. The question remains unanswered, however, as to how these Gli proteins participate in the Shh signaling pathway. In this study, regulatory activities associated with the Gli2 protein were investigated in relation to the Shh signaling. Although Gli2 acts as a weak transcriptional activator, it is in fact a composite of positive and negative regulatory domains. In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator. In transgenic mouse embryos, N-terminally truncated Gli2, unlike the full length protein, activates a Shh target gene, HNF3beta, in the dorsal neural tube, thus mimicking the effect of Shh signal. This suggests that unmasking of the strong activation potential of Gli2 through modulation of the N-terminal repression domain is one of the key mechanisms of the Shh signaling. A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1. When the Shh signal derived from the notochord is received by the neural plate, the widely expressed Gli2 and Gli3 proteins are presumably converted to their active forms in the ventral cells, leading to activation of transcription of their target genes, including Gli1.

A Synopsis of Signaling Crosstalk of Pericytes and Endothelial Cells in Salivary Gland

“…In the absence of HH ligands, PTCH1 suppresses the activity of the transducer Smoothened (SMO) and the downstream transcription factors (TFs), GLI1, GLI2, and GLI3 are connected with Suppressor of fused (SUFU), a negative regulator of HH signaling and Kinesin family member 7 (KIF7) [ 162 , 165 , 166 ]. Notably, GLI1 constitutes the readout of the HH’s scheme, serving as the main downstream effector of the pathway, and also as a target gene [ 167 , 168 , 169 ], inasmuch as GLI2 and GLI3 organize into full-length (FL) as activator and as repressor (GLIR) configurations [ 170 ]. KIF 7 and SUFU sustain the phosphorylation of GLIFL by protein kinaseA (PKA), glycogen synthase kinase3 (GSK3), and casein kinase1(CK1) ([ 162 , 171 ]).…”

“…Under basal conditions, the phosphorylated forms of GLI2 and GLI3 are controlled by proteasome degradation through E3 ubiquitin (UBE3) ligase complex and BTB/POZ protein/Cullin 3 (SPOP/CUL3) to induce GLI2R and GLI3R, the repressor configurations [ 162 , 172 ]. In contrast, the activation of HH signaling through the existence of HH ligand/receptor complex relieves the SMO inhibition that avoids the cleavage of GLI2 and GLI3 and activates the cascade of intracellular events [ 162 ], promoting the release of GLI from SUFU that translocates to the nucleus and activates HH target genes, by regulation of apoptosis ( BCL2 ), cell cycle (CyclinD1(CCND1)), and N-MYC [ 162 , 167 , 173 , 174 ].…”

Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

“…With active HH signalling the full length GLI3 protein undergoes phosphorylation and nuclear translocation, and acts as a transcriptional activator (GLI3-A) on target gene expression. Conversely, when the HH is off, GLI3 is processed by C-terminus truncation into the GLI3-R transcriptional repressor [52] (Figure 1).…”

Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

“…GLI transcription factors have overlapping as well as distinctive functions. In humans, GLI2 is the primary activator, GLI3 (lacking the C-terminal transactivation domain) is the primary repressor [ 80 , 81 ], and GLI1 is a target gene that acts as an activator in a positive feedback loop [ 82 ]. In this study, GLI1 expression resulted as slightly but not significantly increased in untreated NBCCS-HFs and CAFs compared to healthy fibroblasts.…”