Gli Phosphorylation Code in Hedgehog Signal Transduction

Zhou, Mengmeng; Jen, Jin

doi:10.3389/fcell.2022.846927

Cited by 17 publications

(16 citation statements)

References 87 publications

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“…In vertebrates, there are three members of the GLI gene family, i.e., GLI1, GLI2, and GLI3 [49]. In most biological behaviors, GLIs exist as downstream transcription factors of SMO in response to HH signaling [50, 51]. GLI1 and GLI2 primarily function as transcriptional activators and play a positive feedback loop upon pathway activation [52], whereas GLI3 usually function as transcriptional repressor [53].…”

Section: Discussionmentioning

confidence: 99%

Smoothened mediates medaka spermatogonia proliferation via Gli1–Rgcc–Cdk1 axis

Zhao

Liu

et al. 2023

Biology of Reproduction

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The proliferation of spermatogonia directly affect spermatogenesis and male fertility, but its underlying molecular mechanisms are poorly understood. In this study, Smoothened (Smo), the central transducer of Hedgehog signaling pathway, was characterized in medaka (Oryzias latipes), and its role and underlying mechanisms in the proliferation of spermatogonia were investigated. Smo was highly expressed in spermatogonia. In ex vivo testicular organ culture and a spermatogonial cell line (SG3) derived from medaka mature testis, Smo activation promoted spermatogonia proliferation, while its inhibition induced apoptosis. The expression of glioma-associated oncogene homolog 1 (gli1) and regulator of cell cycle (rgcc) was significantly upregulated in SG3 after Smo activation. Furthermore, Gli1 transcriptionally upregulated the expression of rgcc, and Rgcc overexpression rescued cell apoptosis caused by Smo or Gli1 inhibition. Co-immunoprecipitation assay indicated that Rgcc could interact with cyclin dependent kinase 1 (Cdk1) to regulate the cell cycle of spermatogonia. Collectively, our study firstly reveals that Smo mediates the proliferation of spermatogonia through Gli1-Rgcc-Cdk1 axis. In addition, Smo and Gli1 are necessary of the survival of spermatogonia. This study deepens our understanding of spermatogonia proliferation and survival at the molecular level, and provides insights into male fertility control and reproductive diseases treatment.

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Section: Discussionmentioning

confidence: 99%

Smoothened mediates medaka spermatogonia proliferation via Gli1–Rgcc–Cdk1 axis

Zhao

Liu

et al. 2023

Biology of Reproduction

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“…In the absence of Hh ligands, Ptch impedes the transport and localization of Smo in PC [114], leading to phosphorylation and protein cleavage of Gli2 and Gli3 by PKA, CKI and GSK3β to produce repressed forms (Gli2-R and Gli3-R, respectively) [115][116][117][118][119]. Compared to Gli2 and Gli3, Gli1 is primarily regulated at the transcriptional level and is not cleaved into a repressed form.…”

Section: The Canonical and Noncanonical Hh Signaling Pathwaysmentioning

confidence: 99%

The role of Hedgehog and Notch signaling pathway in cancer

Xia

Yang

et al. 2022

Mol Biomed

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Notch and Hedgehog signaling are involved in cancer biology and pathology, including the maintenance of tumor cell proliferation, cancer stem-like cells, and the tumor microenvironment. Given the complexity of Notch signaling in tumors, its role as both a tumor promoter and suppressor, and the crosstalk between pathways, the goal of developing clinically safe, effective, tumor-specific Notch-targeted drugs has remained intractable. Drugs developed against the Hedgehog signaling pathway have affirmed definitive therapeutic effects in basal cell carcinoma; however, in some contexts, the challenges of tumor resistance and recurrence leap to the forefront. The efficacy is very limited for other tumor types. In recent years, we have witnessed an exponential increase in the investigation and recognition of the critical roles of the Notch and Hedgehog signaling pathways in cancers, and the crosstalk between these pathways has vast space and value to explore. A series of clinical trials targeting signaling have been launched continually. In this review, we introduce current advances in the understanding of Notch and Hedgehog signaling and the crosstalk between pathways in specific tumor cell populations and microenvironments. Moreover, we also discuss the potential of targeting Notch and Hedgehog for cancer therapy, intending to promote the leap from bench to bedside.

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“…Protein kinase A-mediated (PKA) phosphorylation of full-length GLI pro-proteins within the primary cilium initiates the processing of GLI proteins into truncated GLI-Rs. [46][47][48][49] Although the presence of truncated GLI proteins is taken as evidence that they are GLI-Rs, additional unknown post-translational processing might be required for GLI3 to form a functional transcriptional repressor. In this scenario, these post-translational modifications would likely enable its interactions with co-factors or a larger repression complex, thus establishing active GLI repression.…”

Section: Possible Role For Protein Kinase A-mediated Regulation Of Gl...mentioning

confidence: 99%

Timing is everything: Transcriptional repression is not the default mode for regulating Hedgehog signaling

Lex

Vokes

2022

BioEssays

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Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been presumed that GLI proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre-patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time.These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre-patterning, digit regulation, and HH-driven disease.

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Gli Phosphorylation Code in Hedgehog Signal Transduction

Cited by 17 publications

References 87 publications

Smoothened mediates medaka spermatogonia proliferation via Gli1–Rgcc–Cdk1 axis

Smoothened mediates medaka spermatogonia proliferation via Gli1–Rgcc–Cdk1 axis

The role of Hedgehog and Notch signaling pathway in cancer

Timing is everything: Transcriptional repression is not the default mode for regulating Hedgehog signaling

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