A network map of netrin receptor UNC5B-mediated signaling

Bhat, Sameer Ahmed; Gurtoo, Sumrati; Deolankar, Sayali Chandrashekhar; Fazili, Khalid Majid; Advani, Jayshree; Shetty, Rohan; Prasad, T. S. Keshava; Andrabi, Shaida; Subbannayya, Yashwanth

doi:10.1007/s12079-018-0485-z

Cited by 10 publications

(11 citation statements)

References 51 publications

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“…On the other hand, expression of human UNC5A to -C is downregulated in many tumor types, including colorectal, breast, ovary, uterus, stomach, lung, and kidney cancers (22). Since netrin-UNC5B signaling is involved in multiple cellular pathways (23) and has diverse roles in normal physiology and in disease development, understanding the regulation and mechanism of this pathway has clinical significance.…”

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confidence: 99%

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner

Bhat

Sarwar

Gillani

et al. 2020

J Virol

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UNC5B is a dependence receptor that promotes survival in the presence of its ligand, netrin-1, while inducing cell death in its absence. The receptor has an important role in the development of the nervous and vascular systems. It is also involved in the normal turnover of intestinal epithelium. Netrin-1 and UNC5B are deregulated in multiple cancers, including colorectal, neuroblastoma, and breast tumors. However, the detailed mechanism of UNC5B function is not fully understood. We have utilized the murine polyomavirus small T antigen (PyST) as a tool to study UNC5B-mediated apoptosis. PyST is known to induce mitotic arrest followed by extensive cell death in mammalian cells. Our results show that the expression of PyST increases mRNA levels of UNC5B by approximately 3-fold in osteosarcoma cells (U2OS) and also stabilizes UNC5B at the posttranslational level. Furthermore, UNC5B is upregulated predominantly in those cells that undergo mitotic arrest upon PyST expression. Interestingly, although its expression was previously reported to be regulated by p53, our data show that the increase in UNC5B levels by PyST is p53 independent. The posttranslational stabilization of UNC5B by PyST is regulated by the interaction of PyST with PP2A. We also show that netrin-1 expression, which is known to inhibit UNC5B apoptotic activity, promotes survival of PyST-expressing cells. Our results thus suggest an important role of UNC5B in small-T antigen-induced mitotic catastrophe that also requires PP2A. IMPORTANCE UNC5B, PP2A, and netrin-1 are deregulated in a variety of cancers. UNC5B and PP2A are regarded as tumor suppressors, as they promote apoptosis and are deleted or mutated in many cancers. In contrast, netrin-1 promotes survival by inhibiting dependence receptors, including UNC5B, and is upregulated in many cancers. Here, we show that UNC5B-mediated apoptosis can occur independently of p53 but in a PP2A-dependent manner. A substantial percentage of cancers arise due to p53 mutations and are insensitive to chemotherapeutic treatments that activate p53. Unexpectedly, treatment of cancers having functional p53 with many conventional drugs leads to the upregulation of netrin-1 through activated p53, which is counterintuitive. Therefore, understanding the p53-independent mechanisms of the netrin-UNC5B axis, such as those involving PP2A, assumes greater clinical significance. Anticancer strategies utilizing anti-netrin-1 antibody treatment are already in clinical trials.

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confidence: 99%

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner

Bhat

Sarwar

Gillani

et al. 2020

J Virol

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“…Unc-5 netrin receptor B (UNC5B) is a ligand-dependent receptor. In absence of netrins, the intracellular death domain is cleaved by caspase 3 and then combined with death associated protein kinase (DAPK) to induce cell apoptosis; however, in the presence of netrins, the death domain is not cleaved, and apoptosis is inhibited 29. The lncRNA LOC28978 (Gene ID: 728978) is named UNC5B antisense RNA 1 (UASR1) and we investigated its function in this study.…”

Section: Resultsmentioning

confidence: 99%

Long non-coding RNA UASR1 promotes proliferation and migration of breast cancer cells through the AKT/mTOR pathway

Cao

et al. 2019

J. Cancer

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Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides that function as regulatory factors in many human diseases, including cancer. However, majority of lncRNAs remain to be characterized. In this study, we characterized a novel lncRNA transcript, named UNC5B antisense RNA1 (UASR1). UASR1 is 647bp in length consisting of two exons. This lncRNA is an antisense of intron 1 of unc-5 netrin receptor B (UNC5B) gene. In breast cancer tissues, UASR1 was upregulated. Ectopic expression of UASR1 promoted proliferation and clonogenic growth of breast cancer cells MCF7 and MDA-MB-231. The migration of these cells also increased as demonstrated by wound healing and transwell assays. In contrast, silencing of UASR1 suppressed cell proliferation and migration. Further studies showed that UASR1 activated AKT and AKT-mediated mTOR signaling pathway to stimulate cell proliferation and growth. In these cells, active pAKT, pTSC2, p4EBP1 and pp70S6K were increased. Taken together, our data suggest that UASR1 plays an oncogenic role in breast cancer cells through activation of the AKT/mTOR signaling pathway, being a novel RNA oncogene.

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“…Though the signaling pathway map of IL-18 is available in KEGG and Reactome pathway database, it currently provides only a generic view of the signaling modules regulated by IL-18. In the current study, we developed a resource of signaling events mediated by IL-18/IL-18R in similar lines to earlier reports on comprehensive signaling maps (Bhat et al 2019;Pinto et al 2018;Subbannayya et al 2014). Our resource contains the complete cascade of IL-18 signaling, including 319 molecules and 402 reactions stimulated by IL-18 through manual annotation of the data mined from the publicly available literature.…”

Section: Introductionmentioning

confidence: 91%

A comprehensive pathway map of IL-18-mediated signalling

Rex

Agarwal

Prasad

et al. 2019

J. Cell Commun. Signal.

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Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and was initially described as an IFN-γ-inducing factor derived from anti-CD3-stimulated T-helper (Th)1 cells. IL-18 plays a significant role in the activation of hematopoietic cell types mediating both Th1 and Th2 responses and is the primary inducer of interferon-γ in these cells. The biological activity of IL-18 is mediated through its binding to the IL-18 receptor complex and activation of nuclear factor-κB (NF-κB), culminating in the production and release of several cytokines, chemokines, and cellular adhesion molecules. In certain cell types, IL-18 also activates mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase/ AKT serine/threonine kinase (PI3K/AKT) signaling modules leading to the production and release of proinflammatory cytokines. IL-18-mediated signaling acts as one of the vital components of the immunomodulatory cytokine networks involved in host defense, inflammation, and tissue regeneration. Albeit its biomedical importance, a comprehensive resource of IL-18 mediated signaling pathway is currently lacking. In this study, we report on the development of an integrated pathway map of IL-18/IL-18R signaling. The pathway map was developed through literature mining from published literature based on manual curation guidelines adapted from NetPath and includes information on 16 protein-protein interaction events, 38 enzyme-catalysis events, 12 protein translocation events, 26 activations/inhibition events, transcriptional regulators, 230 gene regulation events and 84 induced protein expression events. The IL-18 signaling pathway can be freely accessed through the WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP4754).

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A network map of netrin receptor UNC5B-mediated signaling

Cited by 10 publications

References 51 publications

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner

Long non-coding RNA UASR1 promotes proliferation and migration of breast cancer cells through the AKT/mTOR pathway

A comprehensive pathway map of IL-18-mediated signalling

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