Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells.

Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling. Significantly reduced viability was observed in IRS1-silenced cells even upon EGF stimulation showing the critical role of IRS1 in the EGFR signaling network in both malignant and normal pancreatic cells. This study also demonstrated that EGFR binds directly to IRS1 and at least on two tyrosine sites, Y612 and Y896, IRS1 becomes phosphorylated in response to EGF stimulation. Mechanistically, the EGFR-mediated phosphorylation of IRS1 can further activate the MAPK signaling pathway with the recruitment of GRB2 protein. Collectively, in this study, IRS1 was identified as a crucial regulator in the EGFR signaling suggesting IRS1 as a potential target for more durable responses to targeted PDAC therapy.

The involvement of signaling pathways in the pathogenesis of osteoarthritis: An update.

Osteoarthritis (OA) is one of the most common disabling pathologies, characterized by joint pain and reduced function, significantly worsening the quality of life. Even if important progresses have been made in OA research, little is yet known about the precise cellular and molecular mechanisms underlying OA. Understanding dysregulated signaling networks and their crosstalk in OA may offer a strong opportunity for the development of combined targeted therapies. Hence, this review highlights the recent findings on the main pathways involved in OA development, including Wnt, Notch, Hedgehog, MAPK, AMPK, and JAK/STAT, providing insights on current targeted therapies in OA patients' management. The translational potential of this article: The identification of key signaling pathways involved in OA development and the investigation of their signaling crosstalk could pave the way for more effective treatments and improved management of OA patients in the future.

Paradoxical effects of nanomaterials on plants: Phytohormonal perspective exposes hidden risks amidst potential benefits.

The rapid growth of nanotechnology has led to the production of a significant amount of engineered nanomaterials (NMs), raising concerns about their impact on various domains. This study investigates the negative interactions between NMs and phytohormones in plants, revealing the changes in signaling crosstalk, integrated responses and ecological repercussions caused by NM pollution. Phytohormones, which include auxins, cytokinins, gibberellins, abscisic acid, ethylene, jasmonic acid, salicylic acid and brassinosteroids are essential for plant growth, development, and stress responses. This review examines the intricate relationships between NMs and phytohormones, highlighting disruptions in signaling crosstalk, integrated responses, and ecological consequences in plants due to NM pollution. Various studies demonstrate that exposure to NMs can lead to alterations in gene expression, enzyme functions, and ultimately affect plant growth and stress tolerance. Exposure to NMs has the capacity to affect plant phytohormone reactions by changing their levels, biosynthesis, and signaling mechanisms, indicating a complex interrelation between NMs and phytohormone pathways. The complexity of the relationships between NMs and phytohormones necessitates further research, utilizing modern molecular techniques, to unravel the intricate molecular mechanisms and develop strategies to mitigate the ecological consequences of NM pollution. This review provides valuable insights for researchers and environmentalists concerned about the disruptive effects of NMs on regulating phytohormone networks in plants.

Upregulation of CYR61 by TGF-ß and YAP signaling exerts a counter-suppression of hepatocellular carcinoma.

Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.

The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/ß-catenin signaling in cancer.

The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/ß-catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/ß-catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and ß-catenin and supports the phase transition of ß-catenin. Both processes suppress Wnt/ß-catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/ß-catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.

The Axin scaffold protects the kinase GSK3ß from cross-pathway inhibition.

Multiple signaling pathways regulate the kinase GSK3ß by inhibitory phosphorylation at Ser9, which then occupies the GSK3ß priming pocket and blocks substrate binding. Since this mechanism should affect GSK3ß activity toward all primed substrates, it is unclear why Ser9 phosphorylation does not affect other GSK3ß-dependent pathways, such as Wnt signaling. We used biochemical reconstitution and cell culture assays to evaluate how Wnt-associated GSK3ß is insulated from cross-activation by other signals. We found that the Wnt-specific scaffold protein Axin allosterically protects GSK3ß from phosphorylation at Ser9 by upstream kinases, which prevents accumulation of pS9-GSK3ß in the Axin•GSK3ß complex. Scaffold proteins that protect bound proteins from alternative pathway reactions could provide a general mechanism to insulate signaling pathways from improper crosstalk.

Mass Spectrometry and Pharmacological Approaches to Measuring Cooption and Reciprocal Activation of Receptor Tyrosine Kinases.

Receptor tyrosine kinases (RTKs) can show extensive crosstalk, directly and indirectly. Elucidating RTK crosstalk remains an important goal in the clinical combination of anti-cancer therapies. Here, we present mass spectrometry and pharmacological approaches showing the hepatocyte growth factor receptor (MET)-promoting tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) and other membrane receptors in MET-amplified H1993 NSCLC cells. Conversely, in H292 wt-EGFR NSCLC cells, EGFR promotes the tyrosine phosphorylation of MET. Reciprocal regulation of the EGFR and insulin receptor (IR) was observed in the GEO CRC cells, where inhibition of the EGFR drives tyrosine phosphorylation of the insulin receptor. Similarly, in platelet-derived growth factor receptor (PDGFR)-amplified H1703 NSCLC cells, inhibition of the EGFR promotes the tyrosine phosphorylation of the PDGFR. These RTK interactions are used to illustrate basic principles applicable to other RTK signaling networks. More specifically, we focus on two types of RTK interaction: (1) co-option of one RTK by another and (2) reciprocal activation of one receptor following the inhibition of a distinct receptor.

Phytochrome-interacting factor PIF3 integrates phytochrome B and UV-B signaling pathways to regulate gibberellin- and auxin-dependent growth in cucumber hypocotyls.

In Arabidopsis, the photoreceptors phytochrome B (PhyB) and UV-B resistance 8 (UVR8) mediate light responses that play a major role in regulating photomorphogenic hypocotyl growth, but how they crosstalk to coordinate this process is not well understood. Here we report map-based cloning and functional characterization of an ultraviolet (UV)-B-insensitive, long-hypocotyl mutant, lh1, and a wild-type-like mutant, lh2, in cucumber (Cucumis sativus), which show defective CsPhyB and GA oxidase2 (CsGA20ox-2), a key gibberellic acid (GA) biosynthesis enzyme, respectively. The lh2 mutation was epistatic to lh1 and partly suppressed the long-hypocotyl phenotype in the lh1lh2 double mutant. We identified phytochrome interacting factor (PIF) CsPIF3 as playing a critical role in integrating the red/far-red and UV-B light responses for hypocotyl growth. We show that two modules, CsPhyB-CsPIF3-CsGA20ox-2-DELLA and CsPIF3-auxin response factor 18 (CsARF18), mediate CsPhyB-regulated hypocotyl elongation through GA and auxin pathways, respectively, in which CsPIF3 binds to the G/E-box motifs in the promoters of CsGA20ox-2 and CsARF18 to regulate their expression. We also identified a new physical interaction between CsPIF3 and CsUVR8 mediating CsPhyB-dependent, UV-B-induced hypocotyl growth inhibition. Our work suggests that hypocotyl growth in cucumber involves a complex interplay of multiple photoreceptor- and phytohormone-mediated signaling pathways that show both conservation with and divergence from those in Arabidopsis.

Resolving Crosstalk Between Signaling Pathways Using Mathematical Modeling and Time-Resolved Single Cell Data.

Crosstalk between signaling pathways can modulate the cellular response to stimuli and is therefore an important part of signal transduction. For a comprehensive understanding of cellular responses, identifying points of interaction between the underlying molecular networks is essential. Here, we present an approach that allows the systematic prediction of such interactions by perturbing one pathway and quantifying the concomitant alterations in the response of a second pathway. As the observed alterations contain information about the crosstalk, we use an ordinary differential equation-based model to extract this information by linking altered dynamics to individual processes. Consequently, we can predict the interaction points between two pathways. As an example, we employed our approach to investigate the crosstalk between the NF-κB and p53 signaling pathway. We monitored the response of p53 to genotoxic stress using time-resolved single cell data and perturbed NF-κB signaling by inhibiting the kinase IKK2. Employing a subpopulation-based modeling approach enabled us to identify multiple interaction points that are simultaneously affected by perturbation of NF-κB signaling. Hence, our approach can be used to analyze crosstalk between two signaling pathways in a systematic manner.

How cells sense and integrate information from different sources.

Cell signaling is a fundamental cellular process that enables cells to sense and respond to information in their surroundings. At the molecular level, signaling is primarily carried out by transmembrane protein receptors that can initiate complex downstream signal transduction cascades to alter cellular behavior. In the human body, different cells can be exposed to a wide variety of environmental conditions, and cells express diverse classes of receptors capable of sensing and integrating different signals. Furthermore, different receptors and signaling pathways can crosstalk with each other to calibrate the cellular response. Crosstalk occurs through multiple mechanisms at different levels of signaling pathways. In this review, we discuss how cells sense and integrate different chemical, mechanical, and spatial signals as well as the mechanisms of crosstalk between pathways. To illustrate these concepts, we use a few well-studied signaling pathways, including receptor tyrosine kinases and integrin receptors. Finally, we discuss the implications of dysregulated cellular sensing on driving diseases such as cancer. This article is categorized under: Cancer > Molecular and Cellular Physiology Metabolic Diseases > Molecular and Cellular Physiology.

Tiny Drosophila intestinal stem cells, big power.

The signaling pathways are highly conserved between Drosophila and mammals concerning intestinal development, regeneration, and disease. The powerful genetic tools of Drosophila make it a valuable and convenient alternative to answer basic biological questions that can not be addressed using mammalian models. In this review, we discuss recent advances in how we use fly midgut to answer the following key questions: (1) How intestine stem cell niches are established; (2) which factors control asymmetric division of stem cells; (3) how intestinal cells interact with environmental factors, such as tissue damage, microbiota, and diet; (4) how to screen aging/cancer-related factors or drugs by fly intestine stem cells.

Towards a Discovery of a Zinc-Dependent Phosphate Transport Road in Plants.

Owing to the impending global scarcity of high-quality sources of phosphate (Pi) fertilizers, lowering its use in crop production requires improved insights into factors stimulating Pi uptake from the soil as well as the efficacious use by plants. Following decades of extensive research on plants' adaptation to Pi deficiency with mitigated success in the field, a better understanding of how plants exposed to zinc (Zn) deficiency accumulate much more Pi provides a novel strategy in comparison to when plants are grown in Zn-rich soils. In this context, we review current knowledge and molecular events involved in the Pi and Zn signaling crosstalk in plants that will bear great significance for agronomical and rudimentary research applications.

Endocrine therapy resistance: what we know and future directions.

Endocrine resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. When abnormally regulated, molecular signals responsible for cellular proliferation, as well as ER itself, allow for cellular evasion of ER-dependent treatments. Therefore, pharmacological treatments that target these evasion mechanisms are beneficial for the treatment of endocrine-resistant breast cancers. This review summarizes currently understood molecular signals that contribute to endocrine resistance and their crosstalk that stem from mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase/protein kinase B (PI3K/AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinases 4 and 6 (CDK4/6) and aberrant ER function. Recent clinical trials that target these molecular signals as a treatment strategy for endocrine-resistant breast cancer are also highlighted.

A tale of two players: the role of phosphate in iron and zinc homeostatic interactions.

MAIN CONCLUSION: This minireview details the impact of iron-phosphate and zinc-phosphate interactions in plants and provides perspectives for further areas of research regarding nutrient homeostasis. Iron (Fe) and zinc (Zn) are among the most important micronutrients for plant growth and have numerous implications for human health and agriculture. While plants have developed efficient uptake and transport mechanisms for Fe and Zn, emerging research has shown that the availability of other nutrients in the environment influences the homeostasis of Fe and Zn within plants. In this minireview, we present the current knowledge regarding homeostatic interactions of Fe and Zn with the macronutrient phosphorous (P) and the resulting physiological responses to combined deficiencies of these nutrients. Fe and P interactions have been shown to influence root development, photosynthesis, and biological processes aiding Fe uptake. Zn and P interactions also influence root growth, and coordination of Zn-dependent transcriptional regulation contributes to phosphate (Pi) transport in the plant. Understanding homeostatic interactions among these different nutrients is of critical importance to obtain a more complete understanding of plant nutrition in complex soil environments.

Auxin/Cytokinin Antagonistic Control of the Shoot/Root Growth Ratio and Its Relevance for Adaptation to Drought and Nutrient Deficiency Stresses.

The hormones auxin and cytokinin regulate numerous aspects of plant development and often act as an antagonistic hormone pair. One of the more striking examples of the auxin/cytokinin antagonism involves regulation of the shoot/root growth ratio in which cytokinin promotes shoot and inhibits root growth, whereas auxin does the opposite. Control of the shoot/root growth ratio is essential for the survival of terrestrial plants because it allows growth adaptations to water and mineral nutrient availability in the soil. Because a decrease in shoot growth combined with an increase in root growth leads to survival under drought stress and nutrient limiting conditions, it was not surprising to find that auxin promotes, while cytokinin reduces, drought stress tolerance and nutrient uptake. Recent data show that drought stress and nutrient availability also alter the cytokinin and auxin signaling and biosynthesis pathways and that this stress-induced regulation affects cytokinin and auxin in the opposite manner. These antagonistic effects of cytokinin and auxin suggested that each hormone directly and negatively regulates biosynthesis or signaling of the other. However, a growing body of evidence supports unidirectional regulation, with auxin emerging as the primary regulatory component. This master regulatory role of auxin may not come as a surprise when viewed from an evolutionary perspective.

Mineral nutrient signaling controls photosynthesis: focus on iron deficiency-induced chlorosis.

Photosynthetic organisms convert light energy into chemical energy stored in carbohydrates. To perform this process, an adequate supply of essential mineral elements, such as iron, is required in the chloroplast. Because iron plays a crucial role during electron transport and chlorophyll formation, iron deficiency alters photosynthesis and promotes chlorosis, or the yellowing of leaves. Intriguingly, iron deficiency-induced chlorosis can be reverted by the depletion of other micronutrients [i.e., manganese (Mn)] or macronutrients [i.e., sulfur (S) or phosphorus (P)], raising the question of how plants integrate nutrient status to control photosynthesis. Here, we review how improving our understanding of the complex relationship between nutrient homeostasis and photosynthesis has great potential for crop improvement.

RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1.

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.

Hormonal Regulation and Crosstalk of Auxin/Cytokinin Signaling Pathways in Potatoes In Vitro and in Relation to Vegetation or Tuberization Stages.

Auxins and cytokinins create versatile regulatory network controlling virtually all aspects of plant growth and development. These hormonal systems act in close contact, synergistically or antagonistically, determining plant phenotype, resistance and productivity. However, the current knowledge about molecular interactions of these systems is still scarce. Our study with potato plants aimed at deciphering potential interactions between auxin and cytokinin signaling pathways at the level of respective gene expression. Potato plants grown on sterile medium with 1.5% (vegetation) or 5% (tuberization) sucrose were treated for 1 h with auxin or cytokinin. Effects of these two hormones on expression profiles of genes belonging to main signaling pathways of auxin and cytokinin were quantified by RT-qPCR. As a result, several signaling genes were found to respond to auxin and/or cytokinin by up- or down-regulation. The observed effects were largely organ-specific and depended on sucrose content. Auxin strongly reduced cytokinin perception apparatus while reciprocal cytokinin effect was ambiguous and sucrose-dependent. In many cases, functional clustering of genes of the same family was observed. Promoters in some clusters are enriched with canonic hormone-response cis-elements supporting their direct sensitivity to hormones. Collectively, our data shed new light on the crosstalk between auxin- and cytokinin signaling pathways.

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology.

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature.