Smoothened regulation in response to Hedgehog stimulation

Jiang, Kai; Jia, Jianhang

doi:10.1007/s11515-015-1385-8

Cited by 11 publications

(9 citation statements)

References 128 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although Ptch1 inhibits Smo while the pathway is inactive, the binding of the Hh ligand to Ptch1 causes phosphorylation of the Smo receptor, which results in localization of activated Smo onto cell surface, through inhibition of ubiquitination-mediated endocytosis and increased presence of its active conformation (Fig. 1C) (34, 35). Additionally, a required step in the transduction of the Hh pathway is the enrichment of the Smo receptor through intraflagellar transport to the primary cilium, a tightly controlled and activation-dependent event (36–38).…”

Section: Introductionmentioning

confidence: 99%

Role of Sonic Hedgehog Signaling Pathway in Intervertebral Disk Formation and Maintenance

Rajesh

Dahia

2018

Curr Mol Bio Rep

View full text Add to dashboard Cite

a) Purpose of Review: The intervertebral discs (IVD) are an essential component of the spine. Degeneration of the discs, commonly due to age or injury, is a leading cause of chronic lower back pain. Despite its high prevalence, there is no effective treatment for disc disease due to limited understanding of disc at the cellular and molecular level. b) Recent Findings: Recent research has demonstrated the importance of the intracellular developmental pathway sonic hedgehog (Shh) during the formation and postnatal maintenance of the IVD. Recent studies corroborate that the down-regulation of SHH expression is associated with pathological changes in the IVDs and demonstrate the reactivation of the hedgehog pathway as a promising avenue for rescuing health disc structure and function. c) Summary: Understanding the role of developmental signaling pathways that regulate disc formation and maintenance may help develop strategies to recapitulate the same mechanism for disc treatment and hence improve the quality and longevity of patient lives.

show abstract

Section: Introductionmentioning

confidence: 99%

Role of Sonic Hedgehog Signaling Pathway in Intervertebral Disk Formation and Maintenance

Rajesh

Dahia

2018

Curr Mol Bio Rep

View full text Add to dashboard Cite

show abstract

“…Smo acts as a signal transducer whose activity is inhibited by Ptc in the absence of Hh. How Ptc inhibits Smo is not completely understood, although recent studies indicate that phospholipids act in between Ptc and Smo in Drosophila Hh signaling 8 9 10 . Binding of Hh to Ptc alleviates Ptc-mediated inhibition of Smo, allowing Smo to activate Cubitus interuptus (Ci)/Gli transcription factors and ultimately induce the expression of Hh target genes, such as decapentaplegic (dpp ), patched (ptc) , and engrailed (en ) 11 12 .…”

mentioning

confidence: 99%

SUMO regulates the activity of Smoothened and Costal-2 in Drosophila Hedgehog signaling

Zhang

Liu

Jiang

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 destabilizes Smo in a phosphorylation independent manner. Mechanistically, we discover that excessive Krz, the Drosophila β-arrestin 2, inhibits Smo sumoylation and prevents Smo accumulation through Krz regulatory domain. Krz likely facilitates the interaction between Smo and Ulp1 because knockdown of Krz by RNAi attenuates Smo-Ulp1 interaction. Finally, we provide evidence that Cos2 is also sumoylated, which counteracts its inhibitory role on Smo accumulation in the wing. Taken together, we have uncovered a novel mechanism for Smo activation by sumoylation that is regulated by Hh and Smo interacting proteins.

show abstract

“…Studies have shown that Hh induces cell surface accumulation and phosphorylation of Smo by protein kinase A (PKA), casein kinase 1 (CK1), casein kinase 2 (CK2), and G protein-coupled receptor kinase 2 (Gprk2) (Chen and Jiang, 2013;Jiang and Jia, 2015), as well as atypical PKC (aPKC) (Jiang et al, 2014). Differential phosphorylation and gradual conformational change in Smo mediates the transduction of Hh activity gradient (Fan et al, 2012;Zhao et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

An intracellular activation of Smoothened that is independent of Hedgehog stimulation in Drosophila

Jiang

Liu

Zhang

et al. 2018

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Smoothened (Smo), a GPCR family protein, plays a critical role in the reception and transduction of Hedgehog (Hh) signal. Smo is phosphorylated and activated on the cell surface; however, it is unknown whether Smo can be intracellularly activated. Here, we demonstrate that inactivation of the ESCRT-III causes dramatic accumulation of Smo in the ESCRT-III/MVB compartment, and subsequent activation of Hh signaling. In contrast, inactivation of ESCRTs 0-II induces mild Smo accumulation in the ESCRT-III/MVB compartment. We provide evidence that Kurtz (Krz), the β-arrestin2, acts in parallel with the ESCRTs 0-II pathway to sort Smo to the multivesicular bodies and lysosome-mediated degradation. Additionally, upon inactivation of ESCRT-III, all active and inactive forms of Smo are accumulated. Endogenous Smo accumulated upon ESCRT-III inactivation is highly activated, which is induced by phosphorylation but not sumoylation. Taken together, our findings demonstrate a model for intracellular activation of Smo, raising the possibility for tissue overgrowth caused by an excessive amount, rather than mutation of Smo.

show abstract

Smoothened regulation in response to Hedgehog stimulation

Cited by 11 publications

References 128 publications

Role of Sonic Hedgehog Signaling Pathway in Intervertebral Disk Formation and Maintenance

Role of Sonic Hedgehog Signaling Pathway in Intervertebral Disk Formation and Maintenance

SUMO regulates the activity of Smoothened and Costal-2 in Drosophila Hedgehog signaling

An intracellular activation of Smoothened that is independent of Hedgehog stimulation in Drosophila

Contact Info

Product

Resources

About