Mechanisms of Smoothened Regulation in Hedgehog Signaling

Zhang, Jie; Liu, Zulong; Jia, Jianhang

doi:10.3390/cells10082138

Cited by 27 publications

(11 citation statements)

References 93 publications

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“…The Hh signaling is transduced by the seven‐transmembrane protein SMO, which undergoes various posttranslational modifications such as phosphorylation, ubiquitination, and sumoylation, and the mechanisms of SMO regulation are highly conserved among species 18,47 . Our results reveal that ACKR3 regulates SMO phosphorylation and thereby enhances SMO‐induced downstream signaling activation, which is consistent with a previous report showing that phosphorylation‐deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signaling in Drosophila 31 .…”

Section: Discussionsupporting

confidence: 91%

“…45,46 The Hh signaling is transduced by the seven-transmembrane protein SMO, which undergoes various posttranslational modifications such as phosphorylation, ubiquitination, and sumoylation, and the mechanisms of SMO regulation are highly conserved among species. 18,47 Our results reveal that ACKR3 regulates SMO phospho-…”

Section: Ackr3 Potentiates Hh Activity By Upregulating Smo Phosphoryl...mentioning

confidence: 63%

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ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression

Tang

Chen

et al. 2023

Molecular Carcinogenesis

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Renal cell carcinoma (RCC) is the second commonest urological malignant neoplasm and mortality rate of patients with RCC appears to be increasing each year. Thus, further understanding of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. Here, we report that atypical chemokine receptor 3 (ACKR3) orchestrates the Hedgehog (Hh)‐GLI1 signaling to promote RCC progression. The expression of ACKR3 is elevated in RCC tissues, which is associated with malignant and clinical outcomes of RCC, and ACKR3 expression is positively correlated with GLI1 expression in RCC tissues. Mechanically, Hh promotes RCC progression through GLI1‐mediated ACKR3 transcription by the directly binding of GLI1 to ACKR3 gene, while CXCL12–ACKR3 axis simultaneously enhances Hh activation via the binding of ACKR3 to Smoothened (SMO), a receptor in Hh pathway, resulting in the upregulation of SMO phosphorylation that potentiates downstream signal activity and consequently contributes to RCC progression. Thus, our findings may provide with the evidence of developing a novel treatment method with specific target for RCC.

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Section: Discussionsupporting

confidence: 91%

Section: Ackr3 Potentiates Hh Activity By Upregulating Smo Phosphoryl...mentioning

confidence: 63%

ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression

Tang

Chen

et al. 2023

Molecular Carcinogenesis

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“…However, we did not observe that conditioned medium promotes the activation of the Hh-signaling pathway in myoblasts. The Hh signaling pathway is one of the most important signaling pathways involved in development and tissue homeostasis ( 48 ). Our data suggest that mechanical stimulation itself likely substitutes for Hh ligands, or may strengthen the signal of residual Hh ligands that could not be detected by our analysis, to activate Hh response in cilia-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy

Zhu

et al. 2022

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

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Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models— Myogenic factor 5 ( Myf5 ) -Arf-like Protein 3 ( Arl3 ) −/− , Paired box protein Pax-7 ( Pax7 )- Intraflagellar transport protein 88 homolog ( Ift88 ) −/− , and Pax7-Arl3 −/− —by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3 −/− mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3 −/− and Pax7-Arl3 −/− mice or primary isolated Myf5-Arl3 −/− and Pax7-Ift88 −/− myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.

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“…It is initiated by Hh lipoprotein ligand binds to its transmembrane receptor protein patched (Ptch). Then, Ptch is inactivated and relieves smoothening (SMO), resulting in the activation of downstream targets through Gli transcription factors, which are processed from repressors to activators that organize the Hh transcriptional program ( Bangs and Anderson, 2017 ; Zhang et al, 2021 ). GPCR signaling play critical roles in the sensory function of primary cilia ( Schou et al, 2015 ).…”

Section: Cilia Associated Cellular Signallingmentioning

confidence: 99%

INPP5E and Coordination of Signaling Networks in Cilia

Zhang

Tang²,

et al. 2022

Front. Mol. Biosci.

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Primary cilia are ubiquitous mechanosensory organelles that specifically coordinate a series of cellular signal transduction pathways to control cellular physiological processes during development and in tissue homeostasis. Defects in the function or structure of primary cilia have been shown to be associated with a large range of diseases called ciliopathies. Inositol polyphosphate-5-phosphatase E (INPP5E) is an inositol polyphosphate 5-phosphatase that is localized on the ciliary membrane by anchorage via its C-terminal prenyl moiety and hydrolyzes both phosphatidylinositol-4, 5-bisphosphate (PtdIns(4,5)P2) and PtdIns(3,4,5)P3, leading to changes in the phosphoinositide metabolism, thereby resulting in a specific phosphoinositide distribution and ensuring proper localization and trafficking of proteins in primary cilia. In addition, INPP5E also works synergistically with cilia membrane-related proteins by playing key roles in the development and maintenance homeostasis of cilia. The mutation of INPP5E will cause deficiency of primary cilia signaling transduction, ciliary instability and ciliopathies. Here, we present an overview of the role of INPP5E and its coordination of signaling networks in primary cilia.

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Mechanisms of Smoothened Regulation in Hedgehog Signaling

Cited by 27 publications

References 93 publications

ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression

ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression

Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy

INPP5E and Coordination of Signaling Networks in Cilia

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