Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium

Wilson, Christopher W.; Chen, Miao-Hsueh; Chuang, Pao-Tien

doi:10.1371/journal.pone.0005182

Cited by 104 publications

(119 citation statements)

References 39 publications

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“…A number of mutations encoding IFT proteins involved in predominantly primary cilium anterograde IFT have been described, resulting in mice with Hh loss of function phenotypes (Huangfu et al, 2003;Cortellino et al, 2009). Several Hh components, including SMO and Gli molecules, are also present at the primary cilium upon Hh stimulation Rohatgi et al, 2009;Wang et al, 2009;Wilson et al, 2009a). An SMO mutant lacking ciliary translocation blocks Hh signaling (Corbit et al, 2005).…”

Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

“…Gli3 processing is significantly affected by IFT mutants (Huangfu and Anderson, 2005;May et al, 2005;Cortellino et al, 2009), suggesting that SMO activates downstream molecules at the cilium. Current data indicate that localization of SMO to cilium is not sufficient to activate hedgehog signaling (Rohatgi et al, 2009;Wilson et al, 2009a). Using Kif3a tissue-specific gene knockout, recent studies revealed dual roles of cilium for hedgehog signaling carcinogenesis in mouse models Wong et al, 2009).…”

Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

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Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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“…Several studies have now confirmed that Smo appears to concentrate within the primary cilium upon Hh stimulation or upon treatment with pharmacological agents such as cyclopamine or SAG1 that bind Smo and either antagonize or stimulate its activity (22)(23)(24)(25)(26). A prominent concentration of Gli1, Gli2, and Gli3 at the tip of the cilium regardless of treatment with ShhN has been noted in cells virally transduced for expression of these proteins, and endogenous Gli3 has been detected at the ciliary tip in cultured primary limb bud cells in the absence of exogenous Hedgehog stimulation (27).…”

mentioning

confidence: 99%

Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus

Kim

Kato

Beachy

2009

Proc. Natl. Acad. Sci. U.S.A.

304

311

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Stimulation by the extracellular Hedgehog (Hh) protein signal has been shown to alter ciliary localization of the mammalian Hh receptor components Smoothened (Smo) and Patched (Ptc), and mutations that disrupt the structure and function of the cilium also disrupt Hh-induced changes in gene expression. But how ciliary events affect gene expression in the nucleus is not known, and to address this question we have characterized the cellular trafficking of Gli2, the principal mediator of Hh-dependent transcriptional activation. From a combination of pharmacological and genetic manipulations we find in resting cells that both Gli2 and Smo appear to shuttle in and out of the cilium, with Gli2 but not Smo requiring intact cytoplasmic microtubules for ciliary entry and both requiring the ciliary retrograde motor, cytoplasmic dynein 2, for ciliary exit. We also find that changes in ciliary and nuclear trafficking of Gli2 are triggered by the Hh-dependent accumulation of activated Smo in the cilium, resulting in a shift from primarily cytoplasmic localization to accumulation at the distal tip of the cilium and within the nucleus. Gli2 thus functions as a dynamic monitor of Smo activity in the cilium and thereby links Hh pathway activation in the cilium to transcriptional activation in the nucleus.GLi2 ͉ primary cilium ͉ smoothened ͉ trafficking

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“…The PKA phosphorylation sites are not conserved in vertebrate Smo (Zhang et al, 2004). However, recent studies have shown that activation of PKA by cholera toxin or forskolin treatment can induce the accumulation of Smo in the proximal part of the cilium (Wilson et al, 2009;Milenkovic et al, 2009;Wen et al, 2010). Moreover, inhibition of PKA activity using small molecule inhibitors can block Shh-induced activation of ptc1 and gli1 (Milenkovic et al, 2009).…”

Section: Cxcr4a Inhibits Pka Activitymentioning

confidence: 99%

Zebrafish Cxcr4a determines the proliferative response to Hedgehog signalling

et al. 2012

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The Hedgehog (Hh) pathway plays dual roles in proliferation and patterning during embryonic development, but the mechanism(s) that distinguish the mitogenic and patterning activities of Hh signalling are not fully understood. An additional level of complexity is provided by the observation that Hh signalling can both promote and inhibit cell proliferation. One model to account for this apparent paradox is that Hh signalling primarily regulates cell cycle kinetics, such that activation of Hh signalling promotes fast cycling and an earlier cell cycle exit. Here we report that activation of Hh signalling promotes endodermal cell proliferation but inhibits proliferation in neighbouring non-endodermal cells, suggesting that the cell cycle kinetics model is insufficient to account for the opposing proliferative responses to Hh signalling. We show that expression of the chemokine receptor Cxcr4a is a critical parameter that determines the proliferative response to Hh signalling, and that loss of Cxcr4a function attenuates the transcription of cell cycle regulator targets of Hh signalling without affecting general transcriptional targets. We show that Cxcr4a inhibits PKA activity independently of Hh signalling, and propose that Cxcr4a enhances Hh-dependent proliferation by promoting the activity of Gli1. Our results indicate that Cxcr4a is required for Hh-dependent cell proliferation but not for Hh-dependent patterning, and suggest that the parallel activation of Cxcr4a is required to modulate the Hh pathway to distinguish between patterning and proliferation.

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Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium

Cited by 104 publications

References 39 publications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus

Zebrafish Cxcr4a determines the proliferative response to Hedgehog signalling

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