Abstract PR2: A systems biology approach to elucidating the consequences of complex ternary interactions of heparin, FGF ligands, and FGF receptor on downstream signaling in NSCLC cells

Abstract Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular development. We report here that VE-cadherin negatively controls junctional localization and expression of N-cadherin by limiting p120-catenin availability and reducing β-catenin transcriptional activity. Using EC lines expressing either VE or N-cadherin we found that both cadherins inhibit cell proliferation and apoptosis. Both trigger the phosphatidylinositol-3-OH-kinase (PI3K)–AKT-Forkhead-box protein-O1 (FoxO1) pathway and reduce β-catenin transcriptional activity. The extent of signaling correlates with the total level of cadherins regardless of the type of cadherin expressed. In contrast, basal and fibroblast growth factor (FGF)–induced cell motility is promoted by N-cadherin and strongly inhibited by VE-cadherin. This opposite effect is partly because of the ability of VE-cadherin to associate with FGF receptor and the density-enhanced phosphatase-1 (Dep-1) which, in turn, inhibits receptor signaling. We conclude that VE and N-cadherin have both additive and divergent effects on ECs. Differences in signaling are due, in part, to cadherin association with growth factor receptors and modulation of their downstream signaling.

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FGF9 and FGF10 use distinct signaling pathways to direct lung epithelial specification and branching

10.1101/873109 ◽

2019 ◽

Author(s):

Yongjun Yin ◽

David M. Ornitz

Keyword(s):

Signaling Pathways ◽

Lung Development ◽

Lung Epithelial Cells ◽

Epithelial Proliferation ◽

Fgf Receptor ◽

Downstream Signaling ◽

Epithelial Development ◽

Lung Epithelial ◽

Proliferation And Differentiation ◽

Pseudoglandular Stage

AbstractFibroblast Growth Factors (FGFs) 9 and 10 are essential during the pseudoglandular stage of lung development. Mesothelial produced FGF9 is principally responsible for mesenchymal growth, whereas epithelial produced FGF9 and mesenchymal produced FGF10 guide lung epithelial development, and loss of either of these ligands affects epithelial branching. Because FGF9 and FGF10 activate distinct FGF receptors (FGFRs), we hypothesized that they would control distinct developmental mechanisms. Here, we show that FGF9 signaled through epithelial FGF receptor 3 (FGFR3) to directly promote distal epithelial fate specification and inhibit epithelial differentiation. By contrast, FGF10 signaled through epithelial FGFR2b to promote epithelial proliferation and differentiation. Furthermore, FGF9-FGFR3 signaling functionally opposed FGF10-FGFR2b signaling, and FGFR3 preferentially used downstream PI3K pathways, whereas FGFR2b relied on downstream RAS-MAPK pathways. These data demonstrate that within lung epithelial cells, different FGFRs function independently; they bind receptor-specific ligands and direct unique developmental functions through activation of distinct downstream signaling pathways.

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Circulating FGF21 Levels in Human Health and Metabolic Disease

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0879-2968 ◽

2019 ◽

Vol 128 (11) ◽

pp. 752-770 ◽

Cited By ~ 5

Author(s):

Michaela Keuper ◽

Hans-Ulrich Häring ◽

Harald Staiger

Keyword(s):

Metabolic Disease ◽

Plasma Lipids ◽

Therapeutic Potential ◽

Metabolic Effects ◽

Fibroblast Growth Factor 21 ◽

Comprehensive Overview ◽

Fgf Receptor ◽

Downstream Signaling ◽

Beneficial Effects ◽

Receptor Isoforms

AbstractHuman fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21’s role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.

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Induction of chondrocyte growth arrest by FGF: transcriptional and cytoskeletal alterations

Journal of Cell Science ◽

10.1242/jcs.115.3.553 ◽

2002 ◽

Vol 115 (3) ◽

pp. 553-562 ◽

Cited By ~ 3

Author(s):

Orit Rozenblatt-Rosen ◽

Efrat Mosonego-Ornan ◽

Einat Sadot ◽

Liora Madar-Shapiro ◽

Yuri Sheinin ◽

...

Keyword(s):

Bone Growth ◽

Mapk Pathway ◽

Skeletal Development ◽

Growth Arrest ◽

Focal Adhesions ◽

Fgf Receptor ◽

Downstream Signaling ◽

Membrane Microdomain ◽

Human Disorders ◽

Differentiation And Proliferation

The effect of fibroblast growth factor (FGF) on mature chondrocytes, the cells responsible for axial skeletal development, is growth attenuation rather than stimulation. This singular response has been linked to signaling via FGF receptor 3 (FGFR3), partly because mutations causing chronic FGFR3 activation lead to various human disorders of bone growth. In order to study how FGF inhibits growth, we analyzed its effect on a rat chondrocyte-derived cell line. We show that the FGF-induced growth arrest occurs at the G1 phase,accompanied by profound changes in gene expression and cytoskeletal organization. Within minutes of binding, FGF induces tyrosine kinase activity in the focal substrate adhesions where it colocalizes with vinculin. Upon FGF stimulation, FGFR3 is selectively removed from the focal adhesions, which is followed by their disassembly and disruption of the organized cytoskeleton. Multiple genes are induced following FGF stimulation in chondrocytes, which has been shown by DNA array screening and confirmed for some by immunoblotting. These genes include regulators of cell differentiation and proliferation such as c-jun, JunD, cyclin-D1, NFκB1 and of plasma-membrane microdomain morphology, such as ezrin. The transcription factor Id1 is downregulated, consistent with the cells' exit from the mitotic cycle. Moreover, following FGF stimulation, levels of FGFR3 mRNA and protein decline, as does downstream signaling through the MAPK pathway. The importance of this FGFR3-mediated on-off control is illustrated in transgenic mice expressing mutant, hyperactive FGFR3, where abnormally high levels of NFκB are expressed throughout their bone growth-plates. A working model is presented of the signaling network involved in regulating FGF-induced chondrocyte differentiation and receptor downregulation.

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Combining integrated systems-biology approaches with intervention-based experimental design provides a higher-resolution path forward for microbiome research

Behavioral and Brain Sciences ◽

10.1017/s0140525x18002911 ◽

2019 ◽

Vol 42 ◽

Author(s):

J. Alfredo Blakeley-Ruiz ◽

Carlee S. McClintock ◽

Ralph Lydic ◽

Helen A. Baghdoyan ◽

James J. Choo ◽

...

Keyword(s):

Systems Biology ◽

High Resolution ◽

Experimental Design ◽

Integrated Systems ◽

Microbiome Research ◽

Constructive Criticism

Abstract The Hooks et al. review of microbiota-gut-brain (MGB) literature provides a constructive criticism of the general approaches encompassing MGB research. This commentary extends their review by: (a) highlighting capabilities of advanced systems-biology “-omics” techniques for microbiome research and (b) recommending that combining these high-resolution techniques with intervention-based experimental design may be the path forward for future MGB research.

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