Gli Phosphorylation Code in Hedgehog Signal Transduction.

Mengmeng Zhou,Jin Jiang

doi:10.3389/fcell.2022.846927

Abstract

Hedgehog (Hh) family of secreted proteins governs many key processes in embryonic development and adult tissue homeostasis in species ranging from insects to human. Deregulation of Hh signaling has been implicated in a wide range of human diseases including birth defect and cancer. Hh signaling pathway culminates in the conversion of the latent transcription factor Cubitus interruptus (Ci)/Gli from a repressor form (CiR/GliR) into an activator form (CiA/GliA). Both the production of CiR/GliR in the absence of Hh and the formation of CiA/GliA in response to Hh are regulated by phosphorylation. Whereas previous studies demonstrated that sequential phosphorylation by protein kinase A (PKA), glycogen synthase kinase 3 (GSK3), and casein kinase 1 (CK1) at multiple Ser/Thr clusters in the C-terminal region of Ci/Gli targets it for proteolytic processing to generate CiR/GliR, recent studies revealed that phosphorylation of Ci/Gli by the Fused (Fu)/Unc-51 like kinase (Ulk) family kinases Fu/Ulk3/Stk36 and other kinases contributes to Ci/Gli activation. Fu/Ulk3/Stk36-mediated phosphorylation of Ci/Gli is stimulated by Hh, leading to altered interaction between Ci/Gli and the Hh pathway repressor Sufu. Here we review our current understanding of how various Ci/Gli phosphorylation events are regulated and how they influence Hh signal transduction.

Highlights

The Hedgehog (Hh) family of signaling molecules governs embryonic development and adult tissue homeostasis in species ranging from insects to mammals, and aberrant Hh signaling contributes to a wide range of human diseases (Nieuwenhuis and Hui, 2005; Jiang and Hui, 2008; Petrova and Joyner, 2014; Jiang, 2021)
This study found that the elevated basal ciliary cAMP level is due to increased AC5/6 activity induced by PIP3 and that Shh reduces ciliary cAMP levels by promoting calcium influx to inhibit AC5/6 (Moore et al, 2016)
Consistent with a previous finding that CK2 promotes Hh signaling by phosphorylating Cubitus interruptus (Ci)/Gli in addition to Smo (Jia et al, 2010), a recent phosphoproteomics study identified CK2 as critical for the stabilization and transcriptional activity of Gli2 in granule neuron precursors and showed that pharmacological inhibition of CK2 attenuated the growth of Shh-type medulloblastoma cells expressing a drug resistant Smo mutant (Purzner et al, 2018)

Summary

Introduction

The Hedgehog (Hh) family of signaling molecules governs embryonic development and adult tissue homeostasis in species ranging from insects to mammals, and aberrant Hh signaling contributes to a wide range of human diseases (Nieuwenhuis and Hui, 2005; Jiang and Hui, 2008; Petrova and Joyner, 2014; Jiang, 2021). A subsequent study identified two PKA sites in Gli2/3 whose mutations resulted in increased GliA activity (Figure 2) (Niewiadomski et al, 2014).

Results

Conclusion