Activity-Dependent Internalization of Smoothened Mediated by ß-Arrestin 2 and GRK2

@article{Chen2004ActivityDependentIO,
  title={Activity-Dependent Internalization of Smoothened Mediated by {\ss}-Arrestin 2 and GRK2},
  author={Wei Chen and Xiu-rong Ren and Christopher D. Nelson and Larry S. Barak and James K. Chen and Philip A. Beachy and Frederic J. de Sauvage and Robert J. Lefkowitz},
  journal={Science},
  year={2004},
  volume={306},
  pages={2257 - 2260}
}
Binding of Sonic Hedgehog (Shh) to Patched (Ptc) relieves the latter's tonic inhibition of Smoothened (Smo), a receptor that spans the cell membrane seven times. This initiates signaling which, by unknown mechanisms, regulates vertebrate developmental processes. We find that two molecules interact with mammalian Smo in an activation-dependent manner: G protein–coupled receptor kinase 2 (GRK2) leads to phosphorylation of Smo, and β-arrestin 2 fused to green fluorescent protein interacts with Smo… Expand
Regulation of smoothened by Drosophila G-protein-coupled receptor kinases.
TLDR
The results suggest that Smo is regulated by distinct Ptc-dependent and Gprk2-dependent trafficking mechanisms in vivo, analogous to constitutive and activity-dependent regulation of GPCRs. Expand
β-Arrestin–Mediated Localization of Smoothened to the Primary Cilium
TLDR
It is demonstrated that β-arrestins mediate the activity-dependent interaction of Smo and the kinesin motor protein Kif3A and suggested roles for β-Arrestins in mediating the intracellular transport of a 7TMR to its obligate subcellular location for signaling. Expand
Growth Arrest Specific 8 (Gas8) and G Protein-coupled Receptor Kinase 2 (GRK2) Cooperate in the Control of Smoothened Signaling*
TLDR
Gas8 is identified as a positive regulator of Hh signaling that cooperates with GRK2 to control Smo signaling and displays a synergistic effect on zebrafish early muscle development. Expand
Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2
TLDR
It is found that G protein-coupled receptor kinase 2 (GRK2) promotes the association between active Smoothened and β-arrestin 2, and Gli-dependent signaling, mediated by coexpression of Smoothensed and GRK2, is diminished by β-arsenin 2 knockdown with shRNA. Expand
Activation of heterotrimeric G proteins by Smoothened
TLDR
The capacity of mammalian Smo to couple to G proteins directly is evaluated and the data suggest that Smo is in fact the source of two signals relevant to the activation of Gli: one involving Gi and the other involving events at Smo’s C-tail independent of Gi. Expand
Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits
TLDR
This work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus, and may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology. Expand
Dose dependent transduction of Hedgehog relies on phosphorylation-based feedback between the GPCR Smoothened and the kinase Fused
Smoothened (SMO) is a GPCR-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds inExpand
Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits
TLDR
This work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus, and it is shown that this process is more fundamentally similar between species than prevailing hypotheses suggest. Expand
An essential role for Grk2 in Hedgehog signalling downstream of Smoothened
TLDR
It is shown that the response to Hh signalling is effectively abolished in the absence of Grk2 activity, and it is speculated that Grk 2 may regulate Hh pathway activity by downregulation of a GPCR. Expand
A PKA Inhibitor Motif within Smoothened Controls Hedgehog Signal Transduction
TLDR
A new mode of GPCR-PKA communication is defined that may be harnessed by a range of membrane receptors and kinases and echoes one utilized by the Wnt cascade, revealing an unexpected similarity in how these two essential developmental and cancer pathways signal intracellularly. Expand
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References

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Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2.
TLDR
Evidence is presented that Smo associates directly with a Ci-containing complex that is scaffolded and stabilized by the atypical kinesin, Costal-2 (Cos2), which constitutively suppresses pathway activity, but Hh signaling reverses its regulatory effect to promote Ci-mediated transcription. Expand
Small molecule modulation of Smoothened activity
TLDR
It is demonstrated that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action, and four small molecules that directly inhibit Smo activity but are structurally distinct fromcyclopamine are identified. Expand
ß-Arrestin 2 Regulates Zebrafish Development Through the Hedgehog Signaling Pathway
TLDR
It is shown that the functional knockdown of β-arrestin 2 in zebrafish embryos recapitulates the many phenotypes of Hh pathway mutants and suggests that a functional interaction betweenβ-ar Arrestin 2 and Smoothened may be critical to regulate Hh signaling in zbrafish development. Expand
Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog
TLDR
It is proposed that the association of the Cos2 protein complex with Smo at the plasma membrane controls the stability of the complex and allows Ci activation, eliciting its nuclear translocation. Expand
Patched acts catalytically to suppress the activity of Smoothened
TLDR
It is reported that Ptc and Smo are not significantly associated within Hh-responsive cells and it is suggested that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule. Expand
Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail.
TLDR
It is found that Smo lacking its C-terminal tail (C-tail) is inactive, whereas membrane-tethered Smo C-tail has constitutive albeit low levels of Hh signaling activity. Expand
Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.
beta-Arrestins, originally discovered in the context of heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) desensitization, also function in internalization and signaling ofExpand
Smoothened Activates Gαi-mediated Signaling in Frog Melanophores*
TLDR
The findings demonstrate that the human Sonic hedgehog receptor complex can be functionally reconstituted in melanophores and that it is capable of transmembrane signaling by utilizing endogenous Gαi. Expand
The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
beta-Arrestins are versatile adapter proteins that form complexes with most G-protein-coupled receptors (GPCRs) following agonist binding and phosphorylation of receptors by G-protein-coupledExpand
Identification of a Functional Interaction between the Transmembrane Protein Smoothened and the Kinesin-Related Protein Costal2
TLDR
This work fills in the last major gap in the understanding of the Hh signal transduction pathway by suggesting that no intermediate signal is required to connect Smo to the HSC. Expand
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