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1. Host JAK-STAT activity is a target of parasitoid wasp virulence strategies

   https://doi.org/10.1371/journal.ppat.1012349  

   Brantley, Susanna E; Stouthamer, Corinne M; Kr, Pooja; Fischer, Mary L; Hill, Joshua; Schlenke, Todd A; Mortimer, Nathan T (July 2024, PLOS Pathogens)

   Schneider, David S (Ed.)

   Innate immune responses that allow hosts to survive infection depend on the action of multiple conserved signaling pathways. Pathogens and parasites in turn have evolved virulence factors to target these immune signaling pathways in an attempt to overcome host immunity. Consequently, the interactions between host immune molecules and pathogen virulence factors play an important role in determining the outcome of an infection. The immune responses ofDrosophila melanogasterprovide a valuable model to understand immune signaling and host-pathogen interactions. Flies are commonly infected by parasitoid wasps and mount a coordinated cellular immune response following infection. This response is characterized by the production of specialized blood cells called lamellocytes that form a tight capsule around wasp eggs in the host hemocoel. The conserved JAK-STAT signaling pathway has been implicated in lamellocyte proliferation and is required for successful encapsulation of wasp eggs. Here we show that activity ofStat92E, theD.melanogasterSTAT ortholog, is induced in immune tissues following parasitoid infection. Virulent wasp species are able to suppressStat92Eactivity during infection, suggesting they target JAK-STAT pathway activation as a virulence strategy. Furthermore, two wasp species (Leptopilina guineaensisandGanaspis xanthopoda) suppress phenotypes associated with a gain-of-function mutation inhopscotch, theD.melanogasterJAK ortholog, indicating that they inhibit the activity of the core signaling components of the JAK-STAT pathway. Our data suggest that parasitoid wasp virulence factors block JAK-STAT signaling to overcome fly immune defenses. 

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2. The ETS-transcription factor Pointed is sufficient to regulate the posterior fate of the follicular epithelium

   https://doi.org/10.1242/dev.189787  

   Stevens, Cody A.; Revaitis, Nicole T.; Caur, Rumkan; Yakoby, Nir (November 2020, Development)

   null (Ed.)

   The Janus-kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway regulates the anterior posterior axis of the Drosophila follicle cells. In the anterior, it activates the bone morphogenetic protein (BMP) signaling pathway through expression of the BMP ligand, decapentaplegic (dpp). In the posterior, JAK/STAT works with the epidermal growth factor receptor (EGFR) pathway to express the T-box transcription factor midline (mid). While MID is necessary in establishing the posterior fate of the egg chamber, we show that it is not sufficient to determine a posterior fate. The ETS-transcription factor pointed (pnt) is expressed in an overlapping domain to mid in the follicle cells. This study shows that pnt is upstream of mid, and it is sufficient to induce a posterior fate in the anterior end, which is characterized by the induction of mid, the prevention of the stretched cells formation, and the abrogation of border cells migration. We demonstrate that the anterior BMP signaling is abolished by PNT through dpp repression. However, ectopic DPP cannot rescue this repression, suggesting additional targets of PNT participate in the posterior fate determination. 

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3. Applying molecular communication theory to estimate information loss in cell signal transduction: an approach based on cancer transcriptomics

   https://doi.org/10.1145/3233188.3233202  

   Sakkaff, Zahmeeth; Immaneni, Aditya; Pierobon, Massimiliano (September 2018, NANOCOM '18 Proceedings of the 5th ACM International Conference on Nanoscale Computing and Communication)

   Signal transduction pathways are chemical communication channels embedded in biological cells, and they propagate information from the environment to regulate cell growth and proliferation, among other cell's behaviors. Disruptions in the normal functionalities of these channels, mostly resulting from mutations in the underlying genetic code, can be leading causes of diseases, such as cancer. Motivated by the increasing availability of public data on genetic code expression in cell tissue samples, i.e., transcriptomics, and the emerging field of molecular communication, a novel data-driven approach based on experimental data mining and communication theory is proposed in this paper. This approach is an alternative to existing computational models of these pathways in the context of cancer, which often appear to oversimplify the complexity of the underlying mechanisms. In contrast, a computational methodology is here derived to estimate the difference in information propagation performance of signal transduction pathways in healthy and diseased cells, solely based on transcriptomic data. This methodology is built upon a molecular communication abstraction of information flow through the pathway and its correlation with the expression of the underlying DNA genes. Numerical results are presented for a case study based on the JAK-STAT pathway in kidney cancer, and correlated with the occurrence of pathway gene mutations in the available data. 

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4. From network analysis to experimental validation: identification of regulators of non-muscle myosin II contractility using the folded-gastrulation signaling pathway

   https://doi.org/10.1186/s12860-023-00492-3  

   Zhao, Andy; Varady, Sophia; O’Kelley-Bangsberg, Madelyn; Deng, Vicki; Platenkamp, Amy; Wijngaard, Petra; Bern, Miriam; Gormley, Wyatt; Kushkowski, Elaine; Thompson, Kat; et al (October 2023, BMC Molecular and Cell Biology)

   Abstract The morphogenetic process of apical constriction, which relies on non-muscle myosin II (NMII) generated constriction of apical domains of epithelial cells, is key to the development of complex cellular patterns. Apical constriction occurs in almost all multicellular organisms, but one of the most well-characterized systems is the Folded-gastrulation (Fog)-induced apical constriction that occurs inDrosophila. The binding of Fog to its cognizant receptors Mist/Smog results in a signaling cascade that leads to the activation of NMII-generated contractility. Despite our knowledge of key molecular players involved in Fog signaling, we sought to explore whether other proteins have an undiscovered role in its regulation. We developed a computational method to predict unidentified candidate NMII regulators using a network of pairwise protein–protein interactions called an interactome. We first constructed aDrosophilainteractome of over 500,000 protein–protein interactions from several databases that curate high-throughput experiments. Next, we implemented several graph-based algorithms that predicted 14 proteins potentially involved in Fog signaling. To test these candidates, we used RNAi depletion in combination with a cellular contractility assay inDrosophilaS2R + cells, which respond to Fog by contracting in a stereotypical manner. Of the candidates we screened using this assay, two proteins, the serine/threonine phosphatase Flapwing and the putative guanylate kinase CG11811 were demonstrated to inhibit cellular contractility when depleted, suggestive of their roles as novel regulators of the Fog pathway. 

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5. Cytokinin–CLAVATA cross-talk is an ancient mechanism regulating shoot meristem homeostasis in land plants

   https://doi.org/10.1073/pnas.2116860119  

   Cammarata, Joseph; Morales Farfan, Christopher; Scanlon, Michael J.; Roeder, Adrienne H. (April 2022, Proceedings of the National Academy of Sciences)

   Plant shoots grow from stem cells within shoot apical meristems (SAMs), which produce lateral organs while maintaining the stem cell pool. In the model flowering plant Arabidopsis , the CLAVATA (CLV) pathway functions antagonistically with cytokinin signaling to control the size of the multicellular SAM via negative regulation of the stem cell organizer WUSCHEL (WUS). Although comprising just a single cell, the SAM of the model moss Physcomitrium patens (formerly Physcomitrella patens ) performs equivalent functions during stem cell maintenance and organogenesis, despite the absence of WUS-mediated stem cell organization. Our previous work showed that the stem cell–delimiting function of the receptors CLAVATA1 (CLV1) and RECEPTOR-LIKE PROTEIN KINASE2 (RPK2) is conserved in the moss P. patens . Here, we use P. patens to assess whether CLV–cytokinin cross-talk is also an evolutionarily conserved feature of stem cell regulation. Application of cytokinin produces ectopic stem cell phenotypes similar to Ppclv1a , Ppclv1b , and Pprpk2 mutants. Surprisingly, cytokinin receptor mutants also form ectopic stem cells in the absence of cytokinin signaling. Through modeling, we identified regulatory network architectures that recapitulated the stem cell phenotypes of Ppclv1a , Ppclv1b , and Pprpk2 mutants, cytokinin application, cytokinin receptor mutations, and higher-order combinations of these perturbations. These models predict that Pp CLV1 and Pp RPK2 act through separate pathways wherein Pp CLV1 represses cytokinin-mediated stem cell initiation, and Pp RPK2 inhibits this process via a separate, cytokinin-independent pathway. Our analysis suggests that cross-talk between CLV1 and cytokinin signaling is an evolutionarily conserved feature of SAM homeostasis that preceded the role of WUS in stem cell organization. 

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