The Steroid Hormone 20-Hydroxyecdysone via Nongenomic Pathway Activates Ca2+/Calmodulin-dependent Protein Kinase II to Regulate Gene Expression

Jing, Yu-Pu; Liu, Wen; Wang, Jin-Xing; Zhao, Xiao‐Fan

doi:10.1074/jbc.m114.622696

Cited by 22 publications

(17 citation statements)

References 51 publications

(61 reference statements)

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“…Previous work has shown that 20E via ErGPCR1 and ErGPCR2, Gαq, PLC, calcium ion, and CaMKII signaling triggers USP1 phosphorylation and acetylation (P-USP1-Ac) to modulate USP1 binding to EcRE for subsequent gene transcription (16,37). In this work, we further revealed that 20E rapidly up-regulates PKCδ expression via EcRB1 and USP1.…”

Section: In Conclusionsupporting

confidence: 55%

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Chen

Pan

et al. 2017

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

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The nuclear receptor EcRB1, which is activated by the insect steroid hormone 20-hydroxyecdysone (20E), is reportedly phosphorylated by a protein kinase after 20E induction. However, the protein kinase has not been identified, and the significance of EcRB1 phosphorylation is unclear. In this study, we identified a protein kinase C δ (PKCδ) isoform (the E isoform) that phosphorylates EcRB1 in the lepidopteran , a serious agricultural pest worldwide, to promote apoptotic gene expression and apoptosis during metamorphosis. Through activation of the EcRB1/USP1 transcription complex by 20E, expression was up-regulated in several tissues during the metamorphic stage. Knockdown of caused failure to transition from larvae to pupae, prevented tissues from undergoing programmed cell death (PCD), and down-regulated the expression of the transcription factor and the apoptosis executors and The threonine residue at position 1343 of PKCδ was phosphorylated and was critical for its proapoptotic function. Overexpression of the PKCδ catalytic domain was localized to the nuclei in HaEpi cells, which increased caspase-3 activity and apoptosis. PKCδ directly phosphorylated a threonine residue at position 468 in the amino acid sequence of EcRB1. The phosphorylation of EcRB1 was critical for its heterodimeric interaction with the USP1 protein and for binding to the ecdysone response element. The data suggested that 20E up-regulates PKCδ expression to regulate EcRB1 phosphorylation for EcRB1/USP1 transcription complex formation, apoptotic gene transcription, and apoptosis.

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Section: In Conclusionsupporting

confidence: 55%

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Chen

Pan

et al. 2017

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

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“…Inhibition or knockdown of PLCγ blocked 20-hydroxyecdysone induced pupation and caused larval death. Moreover, an IP3R inhibitor blocked the increase in cytosol calcium [88], and blocking the increase in cytosol calcium inhibited 20-hydroxyecdysone induced transcription [88, 89]. These data suggest ecdysone activates an evolutionarily conserved insect anticipatory UPR pathway.…”

Section: Figmentioning

confidence: 99%

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

Shapiro

Livezey

et al. 2016

Trends in Endocrinology & Metabolism

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The endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), plays a key role in regulating intracellular protein homeostasis. The extensively studied reactive mode of UPR activation is characterized by unfolded protein, or other EnR stress, triggering UPR activation. Here we focus on the emerging anticipatory mode of UPR activation in which mitogenic steroid and peptide hormones and other effectors pre-activate the UPR and anticipate a future need for increased protein folding capacity. Mild UPR activation in breast cancer can be protective and contributes to antiestrogen resistance. Hyperactivation of the anticipatory UPR pathway in cancer cells with a small molecule converts it from cytoprotective to cytotoxic, highlighting its potential as a therapeutic target in estrogen receptor positive breast cancer.

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“…Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine-specific protein kinase that is regulated by the Ca 2+ /calmodulin complex [55]. CaMKII expression and phosphorylation increase during metamorphosis in H. armigera [56]. 20E regulates phosphorylation of CaMKII at threonine 290, which induces CaMKII translocation into the nucleus.…”

Section: The 20e Signaling Cascade Via Gpcrsmentioning

confidence: 99%

“…The phosphorylation and nuclear translocation of CaMKII induces the phosphorylation and nuclear export of histone deacetylase 3, thus maintaining USP lysine acetylation at amino acid 303. This modification is necessary for its interaction with EcR to form the transcription complex and for the binding of the EcR-USP complex to EcRE [56]. 20E, through GPCRs, induces intracellular Ca 2+ release, which causes stromal interaction molecule 1 (STIM1) phosphorylation and aggregation.…”

Section: The 20e Signaling Cascade Via Gpcrsmentioning

confidence: 99%

“…An intriguing question is the relationship between the genomic action/pathway and the nongenomic action/pathway. From the studies in H. armigera, the genomic action/pathway of 20E is regulated by the nongenomic action/pathway, because the 20E-induced rapid calcium increase in cells activates protein kinases [52,56], therefore promotes EcR-USP transcription complex formation, which initiates gene transcription in 20E pathway finally [64]. Therefore, the 20E signaling pathway is a GPCR-mediated signaling pathway (20E-GPCR pathway).…”

Section: The Relationship Between Genomic Actions and The Nongenomic mentioning

confidence: 99%

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G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone

Zhao

2020

Cell Commun Signal

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G protein-coupled receptors (GPCRs) are cell membrane receptors for various ligands. Recent studies have suggested that GPCRs transmit animal steroid hormone signals. Certain GPCRs have been shown to bind steroid hormones, for example, G protein-coupled estrogen receptor 1 (GPER1) binds estrogen in humans, and Drosophila dopamine/ecdysteroid receptor (DopEcR) binds the molting hormone 20-hydroxyecdysone (20E) in insects. This review summarizes the research progress on GPCRs as animal steroid hormone cell membrane receptors, including the nuclear and cell membrane receptors of steroid hormones in mammals and insects, the 20E signaling cascade via GPCRs, termination of 20E signaling, and the relationship between genomic action and the nongenomic action of 20E. Studies indicate that 20E induces a signal via GPCRs to regulate rapid cellular responses, including rapid Ca2+ release from the endoplasmic reticulum and influx from the extracellular medium, as well as rapid protein phosphorylation and subcellular translocation. 20E via the GPCR/Ca2+/PKC/signaling axis and the GPCR/cAMP/PKA-signaling axis regulates gene transcription by adjusting transcription complex formation and DNA binding activity. GPCRs can bind 20E in the cell membrane and after being isolated, suggesting GPCRs as cell membrane receptors of 20E. This review deepens our understanding of GPCRs as steroid hormone cell membrane receptors and the GPCR-mediated signaling pathway of 20E (20E-GPCR pathway), which will promote further study of steroid hormone signaling via GPCRs, and presents GPCRs as targets to explore new pharmaceutical materials to treat steroid hormone-related diseases or control pest insects. Graphical abstract

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The Steroid Hormone 20-Hydroxyecdysone via Nongenomic Pathway Activates Ca2+/Calmodulin-dependent Protein Kinase II to Regulate Gene Expression

Cited by 22 publications

References 51 publications

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone

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