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Review
. 2014 Sep:33:63-72.
doi: 10.1016/j.semcdb.2014.05.002. Epub 2014 May 17.

G-protein-coupled receptors, Hedgehog signaling and primary cilia

Saikat Mukhopadhyay  1 , Rajat Rohatgi  2
Affiliations
Review

G-protein-coupled receptors, Hedgehog signaling and primary cilia

Saikat Mukhopadhyay et al. Semin Cell Dev Biol. 2014 Sep.

Abstract

The Hedgehog (Hh) pathway has become an important model to study the cell biology of primary cilia, and reciprocally, the study of ciliary processes provides an opportunity to solve longstanding mysteries in the mechanism of vertebrate Hh signal transduction. The cilium is emerging as an unique compartment for G-protein-coupled receptor (GPCR) signaling in many systems. Two members of the GPCR family, Smoothened and Gpr161, play important roles in the Hh pathway. We review the current understanding of how these proteins may function to regulate Hh signaling and also highlight some of the critical unanswered questions being tackled by the field. Uncovering GPCR-regulated mechanisms important in Hh signaling may provide therapeutic strategies against the Hh pathway that plays important roles in development, regeneration and cancer.

Keywords: G-protein coupled receptors; Hedgehog; Primary cilia; Protein Kinase A.

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Figures

Figure 1
Figure 1. Hh signaling at primary cilia
A model for Hh signaling in the absence (left) or presence (right) of Shh. In the absence of Hh ligands, PKA phosphorylates the Gli proteins (red circles) and initiates their processing to repressor forms (GliR) in a cilia-dependent manner. Gli3R suppresses target genes upon nuclear translocation. Upon binding of Shh with Ptch1, Ptch1 is removed from cilia, and Smo activation results in its accumulation in cilia and the consequent decrease in PKA activity towards the Gli proteins. The recently described Efcab7-Iqce module anchors the Evc-Evc2 complex in a signaling microdomain at the base of cilia, transducing downstream signals for Smo-dependent Gli2 activation [71, 72]. Recent results with Efcab1/Iqce knockouts not inhibiting Gli3 processing but preventing Shh pathway activation [72], and the Shh-dependent removal of Gpr161 from cilia (Figure 2) [10] strongly suggest that the inhibition of Gli3 processing is uncoupled from Gli2 activation downstream of Smo. Gli proteins traffic through the cilia in a Gli-Sufu complex, and activation by Shh results in dissociation of Gli from SuFu, allowing them to enter the nucleus and activated target genes.
Figure 2
Figure 2. Gpr161 functions as a negative regulator of the Hh pathway in the neural tube
Left, Gpr161 localizes to primary cilia in a Tulp3/IFT-A-dependent manner [10]. Constitutive activity of Gpr161 leads to increase in cAMP levels in a Gαs-coupled manner. Gαs also functions as a negative regulator of Hh signaling in the neural tube [60]. Currently, ligands that could modulate Gpr161 activity are unknown. Gpr161 activity in cilia could increase ciliary cAMP pools, resulting in PKA activity in close proximity in the basal body [120], promoting Gli3 processing. Right, Shh activity removes Gpr161 from cilia [10], possibly preventing ciliary activation of PKA. Other factors that modulate Shh-mediated activity include activity of PACAP receptor, PAC1 that can affect global PKA activity in the cerebellar granular progenitor neurons [135], and atypical protein kinase C τ/λ (aPKC-τ/λ) that functions in a positive feedback circuit to phosphorylate and activate Gli1 in the context of basal cell carcinoma [139].
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