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Sphingosine 1-phosphate receptor signaling establishes AP-1 transcriptional factor gradients and permits retinal endothelial specialization

ABSTRACT: Sphingosine 1-phosphate receptor signaling establishes AP-1 transcriptional factor gradients and permits retinal endothelial specialization

PROVIDER: PRJNA593497 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10587200_1.fastq.gz	Fastqsanger.gz
	SRR10587200_2.fastq.gz	Fastqsanger.gz
	SRR10587201_1.fastq.gz	Fastqsanger.gz
	SRR10587201_2.fastq.gz	Fastqsanger.gz
	SRR10587202_1.fastq.gz	Fastqsanger.gz

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Project description:Sphingolipids enforce homeostatic cell growth in eukaryotes1,2. Phytosphingosine triggers an adaptive growth arrest in heat-stressed yeast while ceramide and its precursor/product sphingosine function as tumor suppressors in mammalian cells. Consistent with this, the constrained cyclic analogs of sphingosine FTY720 and SH-BC-893 limit tumor growth in multiple pre-clinical cancer models3,4. However, the protein targets that mediate the anti-neoplastic effects of sphingosine-like molecules remain poorly defined. Here we show that natural and synthetic sphingosine-like compounds engage the protein phosphatase 2A (PP2A) scaffolding subunit PPP2R1A and the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). While sphingosine-like molecules were known to activate PP2A3–6, binding to importins was unexpected. PP2A activation limits nutrient access through effects on endolysosomal trafficking3,7–9, but also triggers the proteasomal degradation of anabolic transcription factors like MYC and the androgen receptor (AR)10,11. Importins are required for oncogenic transcription factors to enter the nucleus and engage their target genes. By activating PP2A and inhibiting importins in parallel, sphingosine-like compounds robustly inhibited prostate cancer drivers YAP, JUN, MYC and the AR as well as other proteins involved in proliferation, metabolism, and protein translation. Sphingosine itself also induced conformational changes in PPP2R1A and KPNB1 and blocked IPO7- and KPNB1-dependent nuclear import. Interestingly, ceramide did not engage these protein targets suggesting that ceramide and sphingosine promote homeostatic cell growth through different mechanisms. These results provide biological insights into the anti-neoplastic actions of sphingosine and related molecules and highlight a possible path towards cancer therapeutics that engage PP2A and importins in parallel, simultaneously targeting multiple difficult-to-drug oncoproteins.

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Sphingosine 1-phosphate receptor signaling establishes AP-1 transcriptional factor gradients and permits retinal endothelial specialization

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