Biology subjects

Honda, T.

Publications and source records attributed to Honda, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomic and phenotypic consequences of long-term isolation and small population size in Yakushima macaques

The relative roles of genetic drift, inbreeding, and natural selection in island evolution have been fundamental themes in evolutionary biology for nearly a century. However, empirical studies have yet to reach a consensus, and research integrating both genotypes and phenotypes in primates remains limited. The present study aims to estimate the demographic history of an island primate population, the Yakushima macaque (Macaca fuscata yakui), and evaluate the genomic and morphological consequences of its isolation. To this end, we conducted population genetic analyses based on whole-genome sequencing and geometric morphometric analyses of cranial shape. Our results indicate that M. f. yakui has been isolated with an effective population size of several thousand individuals for over 100,000 years. Although we detected signatures of purifying selection, deleterious alleles have not been sufficiently purged. The degree of fluctuating asymmetry in males was slightly, yet significantly, higher in M. f. yakui than in mainland populations, whereas this trend was not observed in females. Marginal evidence of directional selection was found for cranial size, but not for shape. Overall, our findings suggest that due to long-term isolation, genetic drift and inbreeding have exerted a substantial influence on shaping genotypic and phenotypic variation in this island population.

evolutionary biology↗

bioRxiv2026

Integrating activation-induced costimulation and cytokine signals enhance TCR-based cell therapies

TCR-based cell therapies offer broad targeting of tumor antigens with high sensitivity but often low durability due to insufficient costimulation (signal 2) and cytokine (signal 3) support. To address this, we developed a dual stimulatory receptor (DSR) consisting of the 4-1BBL ectodomain fused to the thrombopoietin receptor (cMPL) endodomain. DSR engages 4-1BB that is transiently upregulated upon TCR stimulation eliciting signal 2 and simultaneously activates cMPL-driven STAT3/5 phosphorylation providing signal 3. DSR increases the expansion of T cells, preserving their effector function and an effector-associated transcriptional profile upon repeated antigen stimulation. DSR arming significantly improves in vivo antitumor activity of T cells redirected to cancer through engineered TCRs or soluble T-cell engagers in diverse xenograft tumor models by enhancing T cell expansion and persistence post-infusion. These results demonstrate broad utility and establish DSR as a modular receptor for the effective and synchronized delivery of signals 2 and 3 to support TCR-based immunotherapies.

immunology↗

bioRxiv2026

A pooled screening approach reveals bacterial chemoreceptors for short-chain carboxylic acids

Bacterial chemotaxis is a key process in host colonization and virulence, mediated by large repertoires of chemoreceptors. Despite their physiological and ecological importance, mapping these chemoreceptors to their cognate metabolic ligands remains a major challenge due to the vast number of potential interactions. To address this, we developed a pooled screening assay that enriches functional chemoreceptors from a gene library. Using this approach, we identified a previously uncharacterized group of chemoreceptors in Pseudomonas species with Cache_3-Cache_2 domains that sense short-chain C3 carboxylic acids. Sequence and computational structural analyses revealed that these chemoreceptors exhibit domain features similar to a recently reported C1 formate chemoreceptor despite substantial sequence divergence. Functional assays of representative chemoreceptors confirmed robust chemotactic responses to C3 carboxylic acids, with limited responses to formate. Integrating structural and molecular dynamics analyses suggests that increased binding pocket size and altered flexibility, relative to the formate chemoreceptor, facilitate recognition of larger C3 carboxylic acid ligands. Together, our approach provides a simple and scalable framework for mapping ligand-chemoreceptor interactions and enables systematic characterization across diverse metabolites.

microbiology↗

bioRxiv2026

Discovery of new marine species Stentor hondawara and its whole-genome reveal their unique ecology in comparison with freshwater stentors

Stentor is a genus of large ciliates that can be found in ponds, lakes, rivers, and fresh waters all over the world. Since their initial discovery in 1744, Stentor strains have been isolated from all populated continents. To date, over 50 individual strains have been identified, yet not a single isolate from a marine environment has been verified. Over 200 years since the initial description of the Stentor genus, our study entails the first concrete discovery of a fully marine Stentor species, as evidenced by its morphological, ecological, and phylogenetic positioning amongst Stentor. This new marine organism, which we have named Stentor hondawara, was verified to be a new species of the Stentor genus that appears to have fully adapted to a uniquely marine lifestyle in a high-salinity environment. Using comparative genomics analysis between the whole-genome sequences of Stentor hondawara and two freshwater species of Stentor, we further detected several intriguing differences in the enrichment of gene orthologs between the marine Stentor hondawara and the freshwater species, Stentor coeruleus and Stentor pyriformis. The gene groups specifically enriched in Stentor hondawara encode a variety of proteins, including ion channels, pH-responsive proteins, osmoprotectants, amino acid biosynthesis enzymes, and signaling receptors. Additionally, using metagenomics, we detected and isolated, from within our initial genome assembly, the genome of a novel marine bacteria, which we propose is an endosymbiont of Stentor hondawara. This bacterial species is an uncharacterized member of the order Rhodospirillales and appears to be a nutritional factory for the host Stentor hondawara. Taken together, our study provides insight into how Stentor hondawara adapted to a marine environment distinct from the habitats of all the other currently known Stentor species living in freshwater.

evolutionary biology↗

bioRxiv2025

Know Today, Know Tomorrow: Ensemble Forecasting of Wildlife Sightings from Temporal Dynamics

O_LIForecasting encounters between humans and large carnivores has largely relied on mechanistic models driven by causal factors such as food resources and weather. However, for short-term forecasting these approaches implicitly require unrealistically detailed real-time data on many covariates and an almost complete understanding of the underlying causal pathways. As a result, they offer little practical support for short-term, operational decision-making. C_LIO_LIWe developed a short-term forecasting system that predicts end-of-month cumulative bear sightings from the beginning of each month by exploiting temporal autocorrelation without mechanistic assumptions, using an ensemble of multiple components: (i) sequential estimation of daily sighting rates via a non-stationary Poisson process, (ii) seasonal baselines with ratio-based corrections from previous months, and (iii) rule-based transitions among components as daily sightings accumulate. C_LIO_LIApplied to Asiatic black bear (Ursus thibetanus) sighting records from two Japanese regions differing 18-fold in encounter frequency (maximum monthly counts: 83 vs. 1490) and with contrasting seasonal peaks, the ensemble achieved correlations of [≥]0.8 between predicted and observed month-end totals from day 1, increasing to [≥]0.98 by day 20 and substantially outperforming a null model that assumed no seasonal or interannual variation ({Delta}AIC: 477-652). C_LIO_LIAfter controlling for baseline spatial risk and for the region-wide daily bear-forecast level (temporal risk) provided by our ensemble, we detected strongly localized short-term recurrence in bear encounters: prior sightings increased encounter probability within 500 m for up to 3 days, with rapid decay in space and time. C_LIO_LISynthesis and applications. This observation-based ensemble demonstrates that temporal dynamics alone can approach the practical limits of short-term predictability of wildlife encounter rates, without relying on detailed environmental covariates or extensive new data collection. By quantifying both when (daily risk levels) and where (localized hotspots around recent sightings) encounters are most likely, the system offers wildlife agencies and residents an immediately implementable tool for issuing targeted warnings, adjusting outdoor activities, and reducing human injuries in regions experiencing increasing human-carnivore conflict. C_LI

ecology↗

bioRxiv2025

The electrophilic metabolite of kynurenine, kynurenine-CKA, targets C151 in Keap1 to derepress Nrf2.

The Kelch-like ECH-associated protein 1 / Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. The use of purified recombinant BTB domain of Keap1 and its C151S mutant counterpart revealed that Kyn-CKA reacts with wild-type, but not C151S mutant, Keap1-BTB, and at a much faster rate than with the small molecule thiol N-acetyl cysteine, demonstrating Kyn-CKA is targeted to react with C151 by the surrounding protein environment. In close agreement, Kyn-CKA increased the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblast (MEF) cells expressing wild-type Keap1, but its inducer potency was greatly diminished in C151S-Keap1 mutant MEFs. Experiments in WT, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA targets C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.

biochemistry↗

bioRxiv2025

Redeployment of Archaeal ESCRT Systems Reveals Conserved Mechanisms Underlying Eukaryotic Complexity

Eukaryotic ESCRT complexes remodel membranes at the plasma membrane and internal compartments, yet how these systems evolved from prokaryotic precursors functioning at the cellular membrane remains unresolved. Here, we show that ESCRT-II, ESCRT-III, VPS4, and ubiquitin from Candidatus Prometheoarchaeum syntrophicum (MK-D1), an Asgard archaeon closely related to eukaryotes, are recruited to canonical ESCRT sites in human cells, including centrosomes, midbodies, nuclear envelopes, endosomes despite the absence of these structures from MK-D1 morphology. In addition to MK-D1 ESCRT II recruitment at these regions, MK-D1 ESCRT-III and VPS4 form ring assemblies at midbodies and target reforming nuclear envelope regions. Futhermore, expression of MK-D1 ESCRT modules enhances efficiency of viral budding in human cells. These findings provide direct experimental evidence that archaeal ESCRT modules integrate into diverse eukaryotic structures, supporting a model in which ancestral membrane-remodeling systems were redeployed during eukaryogenesis to organize novel internal architectures.

evolutionary biology↗

bioRxiv2024

CRAGE-RB-PI-seq enables transcriptional profiling of rhizobacteria during plant-root colonization

Plant roots release a wide array of metabolites into the rhizosphere, shaping microbial communities and their functions. While metagenomics has expanded our understanding of these communities, little is known about the physiology of their members in host environments. Transcriptome analysis via RNA sequencing is a common approach to learning more, but its use has been challenging because plant RNA masks bacterial transcripts. To overcome this, we developed randomly-barcoded promoter-library insertion sequencing (RB-PI-seq) and combined it with chassis-independent recombinase assisted genome engineering (CRAGE), using Pseudomonas simiae WCS417 as a model rhizobacterium. This method enables targeted amplification of barcoded transcripts, bypassing plant RNA interference and allowing measurement of thousands of promoter activities during root colonization. Our analysis revealed time-resolved dynamics of promoter activities, highlighting early transcriptional reprogramming as a key determinant of successful colonization. Additionally, we discovered that transcriptional activation of xanthine dehydrogenase and a lysozyme inhibitor are crucial for evading plant immune system defenses. This framework is scalable to other bacterial species and provides new opportunities for understanding rhizobacterial gene regulation in native environments.

microbiology↗

bioRxiv2024

The physiology of deterrence: Flicker vertigo and its application in avian management

Human-bird conflicts are in a critical state, involving economic losses such as agricultural losses, bird strikes on aircraft and avian influenza. Traditional technologies leveraging bird vision and hearing often lose their effectiveness over time as birds become habituated to these stimuli. To address these challenges, our study introduces a novel countermeasure technology based on neurophysiology. The human brain reacts to flickering light, which can cause symptoms like headaches, nausea, and dizziness. In extremely rare cases, it can even lead to epilepsy. This led us to consider the possibility that similar stimuli could be applicable to birds. In our experiments conducted during the day, we used long-range flashlights. White flickering light had no effect on bird escape behavior. However, when cellophane film was attached to the flashlights to restrict the wavelength, the emitted red light induced escape behavior in birds. Additionally, employing two types of flashlights to generate flickering red+blue or red+green lights elicited escape behavior. However, the blue and green combination proved to be less effective. These results are highly similar to those found in human neurophysiology, showing that red light alone and the combination of red and blue lights have the most significant impact on the brain. By measuring the flight initiation distance (FID) of birds, we found that illuminated areas had a significantly higher FID (137m) compared to non-illuminated areas (12m). These findings suggest that applying principles of human physiology to wildlife management can offer new solutions for bird damage control.

ecology↗

bioRxiv2024

Integrating neurophysiological insights into effective bird deterrence using flickering light

There are few effective methods to mitigate the economic or health-related disadvantages caused by birds. Traditional countermeasures employing sound and light have been utilized for mitigating crop damage, but their efficacy is insufficient, and human-avian conflicts persist. This study explores a fundamentally different approach to resolving these conflicts. Flashing lights that alternate between red and blue are known to stimulate the human brain and can potentially cause photosensitive epilepsy in one in 100,000 people, though very rarely. A 15 Hz flashing stimulus is known to elicit a significant response in humans; however, the optimal flashing pattern for birds remained unclear. We investigated the effect of different flickering patterns, specifically 12.5, 15, and 20 Hz, on crows when illuminated from a distance within 200 meters. The flashlight used was a long-range model and the Light Emitting Diodes (LEDs) consumed about 9 watts of power. The power was supplied by 21700 type lithium-ion batteries. Using a long-range flashlight during daylight, we determined that a 15 Hz flashing stimulus was most effective. This finding suggests that the most intense stimulus identified in human physiology can be equally effective when applied to birds. Survival analysis estimated that by projecting this pattern from a distance of 100 meters, crows fled within 8.1 seconds. Unlike traditional bird damage control techniques that rely on neophobia, this study utilizes physiological aversion. In this regard, our approach is fundamentally different from traditional techniques. The method of using flashing light to stimulate the brain, rather than the eyes, is based on insights from human medical and physiological studies. These findings elucidate the principle of a novel aversive stimulus using flashing light, which holds potential for widespread application in mitigating bird-related issues.

ecology↗

bioRxiv2023

A unified open-source platform for multimodal neural recording and perturbation during naturalistic behavior

Behavioral neuroscience faces two conflicting demands: long-duration recordings from large neural populations and unimpeded animal behavior. To meet this challenge, we developed ONIX, an open-source data acquisition system with high data throughput (2GB/sec) and low closed-loop latencies (<1ms) that uses a novel 0.3 mm thin tether to minimize behavioral impact. Head position and rotation are tracked in 3D and used to drive active commutation without torque measurements. ONIX can acquire from combinations of passive electrodes, Neuropixels probes, head-mounted microscopes, cameras, 3D-trackers, and other data sources. We used ONIX to perform uninterrupted, long ([~]7 hours) neural recordings in mice as they traversed complex 3-dimensional terrain. ONIX allowed exploration with similar mobility as non-implanted animals, in contrast to conventional tethered systems which restricted movement. By combining long recordings with full mobility, our technology will enable new progress on questions that require high-quality neural recordings during ethologically grounded behaviors.

neuroscience↗

bioRxiv2023

Akr1b7 functions as a master regulator in ovarian aging

At the beginning of ovarian aging, the ovulation of immature oocytes is accelerated, leading to the arrest of ovulation despite the remaining oocytes. Here, RNA expression in the ovarian aging of mice is comprehensively analyzed during the estrous cycle after ovulation stimulation. The aldo-keto reductase Akr1b7 pathway transiently activated in the ovaries of young mice disappears in those of old mice. Akr1b7--/-- mice attenuate oocyte Akt activation essential for the follicular development in primordial follicles, and enhanced ovulation in immature oocytes. The estrous cycle is extended because of the prolonged diestrous stage by a sustained progesterone level in Akr1b7--/--mice ovaries, which is caused by the decline of Cyp17a1, a major metabolic enzyme of progesterone in Akr1b7-expressed theca cell layers. In summary, the decreased Akr1b7 pathway causes ovulation of immature oocytes and a prolonged estrous cycle, typical symptoms of ovarian aging.

molecular biology↗

bioRxiv2022

An attenuated vaccinia vaccine encoding the SARS-CoV-2 spike protein elicits broad and durable immune responses, and protects cynomolgus macaques and human ACE2 transgenic mice from SARS-CoV-2 and its variants

As long as the coronavirus disease 2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently needed. We have developed a vaccine (rDIs-S) consisting of the attenuated vaccinia virus DIs strain platform carrying the SARS-CoV-2 S gene. rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin converting enzyme 2 (hACE2) transgenic mice, and showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA. 1 variant (TY38-839). Using a tandem mass tag (TMT) -based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that rDIs-S maintains S protein-specific antibody titers for at least 6 months after a 1st vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current and possibly future variants.

microbiology↗

bioRxiv2022

Circulating mast cell progenitors migrate to atopic dermatitis-like skin then adapt locally

BackgroundMast cells (MCs) are tissue-resident immune cells that are classified into two subsets in mice: connective tissue-type MCs (CTMCs) and mucosal type MCs (MMCs). Although both CTMCs and MMCs can be induced from bone marrow (BM)-derived hematopoietic stem cells (HSCs) in vitro, recent research on MC ontogeny has revealed that MMCs are maintained with a supply of BM-derived HSCs, while CTMCs are maintained locally by self-proliferation in steady state in vivo. However, how CTMCs, such as skin MCs, are maintained in an inflammatory state such as atopic dermatitis (AD) remains to be fully elucidated. Methods: MC903-induced AD model was used to identify BM-derived MCs in the skin. The infiltration and proliferation of MCs were evaluated by flow cytometry using CD45.1 BM-chimera mice and parabiosis. BM-derived MCs in AD-like skin were compared to resident MCs (rMCs) in gene expressions by RNA sequence analysis. The fate of BM-derived MCs in AD-like skin was investigated for expressions of CTMC markers and responses to compound 48/80. Results: In AD-like skin, significant increase of both rMCs and BM-derived MCs was observed. BM-derived MCs were derived from circulating MC progenitors (MCps) and were distinguished from rMCs by integrin{beta}7 expression, which was gradually downregulated in the skin. RNA sequence analysis showed that integrin{beta}7+ MCs in the skin shared characteristics of both MMC and CTMC. Integrin{beta}7+ MCs proliferated in situ and acquired the CTMC phenotypes in AD-like skin. Conclusions: Skin MCs are maintained in AD-like skin by both local proliferation of rMCs and infiltration/proliferation of BM-derived MCs, which differentiate toward CTMC in the skin.

immunology↗

bioRxiv2021

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, are potent BACH1 inhibitors

The transcription factor BACH1 is a potential target against a variety of chronic conditions linked to oxidative stress and inflammation, and formation of cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2- cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these drugs may have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of CDDO-derivatives, but not CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-derivatives inhibit BACH1, which explains the much higher potency of CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-derivatives inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. Altogether, our study identifies CDDO-derivatives as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

cell biology↗

bioRxiv2021

Coordination of gene expression with cell size enables Escherichia coli to efficiently maintain motility across conditions

To swim and navigate, motile bacteria synthesize a complex motility machinery involving flagella, motors, and a sensory system. A myriad of studies has elucidated the molecular processes involved, but less is known about the coordination of motility expression with cellular physiology: In Escherichia coli, motility genes are strongly upregulated in nutrient-poor conditions compared to nutrient-replete conditions; yet a quantitative link to cellular motility has not been developed. Here, we systematically investigate gene expression, swimming behavior, and cell growth across a broad spectrum of exponential growth condition. We establish that E. coli up-regulates the expression of motility genes at slow growth to compensate for reduction in cell size, such that the number of flagella per cell is maintained across conditions. The observed 4-5 flagella per cell is the minimum number needed to keep the majority of cells motile. This simple regulatory objective allows E. coli cells to remain motile across a broad range of growth conditions while keeping the biosynthetic and energetic demands to establish and drive the motility machinery at the minimum needed. Given the strong reduction in flagella synthesis resulting from cell size increases at fast growth, our findings also provide a novel physiological perspective on bacterial cell size control: A larger cell-size at fast growth is an efficient strategy to increase the allocation of cellular resources to the synthesis of those proteins required for fast growth, while maintaining processes such as motility which are only needed on a per-cell basis.

microbiology↗

bioRxiv2020

Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity.

Inorganic arsenic (iAs) is a naturally occurring metalloid present in drinking water and polluted air exposing millions of people globally. Epidemiological studies have linked iAs exposure to the development of numerous diseases including cognitive impairment, cardiovascular failure and cancer. Despite intense research, an effective therapy for chronic arsenicosis has yet to be developed. Laboratory studies have been of great benefit in establishing the pathways involved in iAs toxicity and providing insights into its mechanism of action. However, the in vivo analysis of arsenic toxicity mechanisms has been difficult by the lack of reliable in vivo biomarkers of the effects of iAs. To resolve this issue we have applied the use of our recently developed stress reporter models to study iAs toxicity. The reporter mice Hmox1 (oxidative stress/inflammation; HOTT) and p21 (DNA damage) were exposed to iAs at acute and chronic, environmentally relevant, doses. We observed induction of the oxidative stress reporters in several cell types and tissues, which was largely dependent on the activation of transcription factor NRF2. We propose that our HOTT reporter model can be used as a surrogate biomarker of iAs-induced oxidative stress, and it constitutes a first-inclass platform to develop treatments in arsenicosis. Indeed, in a proof of concept experiment, the HOTT reporter mice were able to predict the therapeutic utility of the antioxidant N-acetyl cysteine in the prevention of iAs associated toxicity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Aberrant claudin-6-adhesion signal promotes endometrial cancer progression via estrogen receptor α

Cell adhesion proteins not only maintain tissue integrity but also possess signaling abilities to organize diverse cellular events in physiological and pathological processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family often possesses aberrant expression in various cancers, but the biological relevance and molecular basis have not yet been established. Here, we show that high CLDN6 expression promotes endometrial cancer progression and represents the poor prognostic marker. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFKs) and to stimulate malignant phenotypes. Importantly, we demonstrate that the CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signalings target Ser518 in the human estrogen receptor and ligand-independently activate target genes in endometrial cancer cells, resulting in cancer development. The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.

cancer biology↗