Semaphorin activates Hippo signaling to control cell growth
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ABSTRACT:
PROVIDER: PRJNA580522 | ENA |
REPOSITORIES: ENA
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Project description:Semaphorins play critical roles in the tumorigenesis of various organs. Originally identified as neuronal axonal guidance molecules and developmental regulators of the nervous and the vascular systems, class 3 Semaphorins (SEMA3s) act through their receptors Plexin As (PLXNAs) and co-receptors Neuropilins (NRPs) to control various processes such as axon growth cone directionality, cell cycle, and angiogenesis. Deletion or silencing of SEMA3B and SEMA3F genes has been observed in lung cancer, metastatic breast cancer, renal carcinoma, and many other malignancies; however, the downstream effectors of SEMA3 in tumorigenesis are still unclear. Here we show that the Hippo pathway is a key mediator of SEMA3’s tumor suppressive function. SEMA3 activates the Hippo pathway to control gene expression and inhibit cell growth. Restoration of SEMA3B expression in lung cancer cells that harbor SEMA3B deletion or silencing suppressed anchorage-independent growth and xenograft formation in a Hippo pathway-dependent manner. Mechanistically, PLXNA promotes the interaction and activation of p190RhoGAPs (ARHGAP5 and ARHGAP35) by the RND GTPase. Activated ARHGAP5/35 in turn act through RhoA and the Hippo kinase cascade to phosphorylate and inactivate YAP and TAZ, the transcriptional co-activators and key effectors of the Hippo pathway. Cancer-associated mutations of RND or ARHGAP5/35 compromised cellular responses to SEMA3, as indicated by YAP phosphorylation and cell growth inhibition. Our study defines a new role of the Hippo pathway in SEMA3 signaling as well as a mechanism for the tumor suppressive function of Semaphorins.
2022-06-21 | GSE139630 | GEO
Project description:Hippo signaling instructs ectopic but not normal organ growth
| PRJNA870441 | ENA
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.
2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress
Project description:Semaphorins were originally identified as axonal guidance molecules, but they also control processes such as vascular development and tumorigenesis. The downstream signaling cascades of Semaphorins in these biological processes remain unclear. Here, we show that the class 3 Semaphorins (SEMA3s) activate the Hippo pathway to attenuate tissue growth, angiogenesis, and tumorigenesis. SEMA3B restoration in lung cancer cells with SEMA3B loss of heterozygosity suppresses cancer cell growth via activating the core Hippo kinases LATS1/2 (large tumor suppressor kinase 1/2). Furthermore, SEMA3 also acts through LATS1/2 to inhibit angiogenesis. We identified p190RhoGAPs as essential partners of the SEMA3A receptor PlexinA in Hippo regulation. Upon SEMA3 treatment, PlexinA interacts with the pseudo-guanosine triphosphatase (GTPase) domain of p190RhoGAP and simultaneously recruits RND GTPases to activate p190RhoGAP, which then stimulates LATS1/2. Disease-associated etiological factors, such as genetic lesions and oscillatory shear, diminish Hippo pathway regulation by SEMA3. Our study thus discovers a critical role of Hippo signaling in mediating SEMA3 physiological function.
| S-EPMC9132450 | biostudies-literature
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.
2023-11-17 | GSE241402 | GEO
Project description:Hippo signaling instructs ectopic but not normal organ growth [Drosophila NonPupatingLarvae]
| PRJNA870446 | ENA
Project description:Hippo signaling instructs ectopic but not normal organ growth [Drosophila YkiHyper]
| PRJNA870447 | ENA
Project description:Hippo signaling instructs ectopic but not normal organ growth [Liver YapHyper]
| PRJNA870448 | ENA
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.
2013-12-31 | GSE49384 | GEO
Project description:Hippo signaling instructs ectopic but not normal organ growth [Liver YapTazKO+CCl4]
| PRJNA870449 | ENA