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: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: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: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:CDK5 activates Hippo signaling to confer resistance to radiotherapy via upregulating TAZ in lung cancer
| PRJNA624894 | ENA
Project description:Skeletal muscles are comprised of gigantic multinucleated cells called muscle fibers, which often span several centimetres in length. Each muscle fiber is densely packed with contractile force-producing myofibrils and ATP-producing mitochondria. During animal development the size of the individual muscle fibers must dramatically increase to match the growth of the animal and to connect growing skeletal elements. How such dramatic tissue growth is coordinated with growth of the contractile apparatus in the muscle fibers is not well understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled during development. We isolated flight muscles from Drosophila melanogaster pupae at 24 h and 32 h APF of the genotypes wt, Dlg5-IR, Slmap-IR, Yorkie-CA, Hippo-IR and isolated total RNA for subsequent BRB-seq sequencing. Our study reveals that regulated activity of core members of the Hippo pathway, Hippo, Warts and Yorkie is required to support post-mitotic flight muscle growth. Interestingly, we identify Dlg5 and Slmap as important members of the STRIPAK phosphatase complex, which negatively regulates Hippo activity and therefore enables post-mitotic muscle growth. Mechanistically, we find that the Hippo pathway controls the timing and the levels of sarcomeric gene expression during muscle development and thus regulates the key components that mediate muscle fiber growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved in mammals a similar mechanism may contribute to skeletal muscle or cardiac growth in humans.
2020-10-03 | GSE158957 | GEO
Project description:Although Semaphorin 3G has some roles in the development of vessels, the roles in immune system are not characterized. We aimed to study how Semaphorin 3G affects the function of macrophages.
2022-05-17 | GSE176438 | GEO
Project description:The Hippo signaling pathway has become recognized as a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to human. In this study, we sought to understand whether Hippo signaling plays a role in pancreatic development and organ homeostasis. We analyzed mRNA from 5 samples each from control and DKO mouse pancreas using Affymetrix MouseGene 1.0 ST Array platfrom. Array data was processed by Affymetrix array computational tools.
2013-02-14 | E-GEOD-44298 | biostudies-arrayexpress
Project description:Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway. Cell lines stably expressing YAP, YAP/TEAD4-S, YAP/TEAD4-FL, YAP/RBM4 and control vector were created, and the total RNA was purified from the cells using TRIzol reagents. The polyadenylated RNAs were purified for construction of sequencing library using kapa TruSeq Total RNA Sample Prep kits (UNC High Throughput Sequencing Facility).
2016-06-16 | E-GEOD-80372 | biostudies-arrayexpress
Project description:The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.
2020-10-07 | GSE82106 | GEO