A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668616 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12807719_1.fastq.gz | Fastqsanger.gz | |||
| SRR12807719_2.fastq.gz | Fastqsanger.gz | |||
| SRR12807720_1.fastq.gz | Fastqsanger.gz | |||
| SRR12807720_2.fastq.gz | Fastqsanger.gz | |||
| SRR12807721_1.fastq.gz | Fastqsanger.gz |
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Project description:As a classic tumor suppressor pathway, Hippo signaling axis is activated by various extra-pathway factors to regulate cell differentiation and organ development. However, recent studies have reported that the activation of Hippo signaling pathway may be more dependent on the autophosphorylation of its core kinase cassette. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) is involved in inducing the inactivation of Hippo signaling pathway in pancreatic cancer. Our study shows that the initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated at arginine-461 (R461) and arginine-467 (R467) in the SARAH domain by PRMT5, and the methylated MST2 suppresses its autophosphorylation and kinase activity by blocking the formation of homodimer, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also discover that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human-derived pancreatic cancer xenografts in immunodeficient mice, which provides a theoretical foundation for the clinical application of PRMT5 inhibitor in pancreatic cancer.
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Project description:Forming biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signaling transduction and gene activation through condensate formation and how dysregulation of these mechanisms contributes to disease progression remain elusive. Here we report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to nucleus and forms phase-separated condensates upon activation of cAMP signaling. We show that CRTC2 interacts with positive transcription elongation factor b (P-TEFb), and cAMP-induced CRTC2 condensate formation activates P-TEFb by extracting P-TEFb from its inhibitory complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). We demonstrate that, in contrast to a dispersed cytosolic distribution in the normal tubular epithelia cells, CRTC2 localizes in nucleus and forms condensates in cystic epithelial cells of mouse and human ADPKD kidneys. We show that genetic depletion of CRTC2 markedly suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, we identify CRTC2-regulated cystogenic genes, whose activation depends on CRTC2 condensation-facilitated P-TEFb recruitment and RNA polymerase II pausing release. Together, our findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and promotes cystogenesis in ADPKD.
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Project description:Forming biomolecular condensates by phase separation has recently emerged as a new principle for regulating gene expression in response to extracellular signaling. However, the molecular mechanisms underlying the coupling of signaling transduction and gene activation through condensate formation and how dysregulation of these mechanisms contributes to disease progression remain elusive. Here we report that CREB-regulated transcription coactivator 2 (CRTC2) translocates to nucleus and forms phase-separated condensates upon activation of cAMP signaling. We show that CRTC2 interacts with positive transcription elongation factor b (P-TEFb), and cAMP-induced CRTC2 condensate formation activates P-TEFb by extracting P-TEFb from its inhibitory complex. Aberrantly elevated cAMP signaling plays central roles in the development of autosomal dominant polycystic kidney disease (ADPKD). We demonstrate that, in contrast to a dispersed cytosolic distribution in the normal tubular epithelia cells, CRTC2 localizes in nucleus and forms condensates in cystic epithelial cells of mouse and human ADPKD kidneys. We show that genetic depletion of CRTC2 markedly suppresses cyst growth in an orthologous ADPKD mouse model. Using integrative transcriptomic and cistromic analyses, we identify CRTC2-regulated cystogenic genes, whose activation depends on CRTC2 condensation-facilitated P-TEFb recruitment and RNA polymerase II pausing release. Together, our findings elucidate a mechanism by which CRTC2 nuclear condensation conveys cAMP signaling to transcription elongation activation and promotes cystogenesis in ADPKD.
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Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.
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