Molecular Networks in FGF Signaling: Flotillin-1 and Cbl-Associated Protein Compete for the Binding to Fibroblast Growth Factor Receptor Substrate 2

Fibroblast growth factor receptor substrate 2 (FRS2α) is a signaling adaptor protein that regulates downstream signaling of many receptor tyrosine kinases. During signal transduction, FRS2 can be both tyrosine and threonine phosphorylated and forms signaling complexes with other adaptor proteins and tyrosine phosphatases. We have here identified flotillin-1 and the cbl-associated protein/ponsin (CAP) as novel interaction partners of FRS2. Flotillin-1 binds to the phosphotyrosine binding domain (PTB) of FRS2 and competes for the binding with the fibroblast growth factor receptor. Flotillin-1 knockdown results in increased Tyr phosphorylation of FRS2, in line with the inhibition of ERK activity in the absence of flotillin-1. CAP directly interacts with FRS2 by means of its sorbin homology (SoHo) domain, which has previously been shown to interact with flotillin-1. In addition, the third SH3 domain in CAP binds to FRS2. Due to the overlapping binding domains, CAP and flotillin-1 appear to compete for the binding to FRS2. Thus, our results reveal a novel signaling network containing FRS2, CAP and flotillin-1, whose successive interactions are most likely required to regulate receptor tyrosine kinase signaling, especially the mitogen activated protein kinase pathway

Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it?

Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins. Its expression is induced by a number of factors including TGF-β. It has been associated with fibrosis in various tissues including the kidney. Diabetic nephropathy (DN) develops in about 30% of patients with diabetes and is characterized by thickening of renal basement membranes, fibrosis in the glomerulus (glomerulosclerosis), tubular atrophy and interstitial fibrosis, all of which compromise kidney function. This review examines changes in CTGF expression in the kidney in DN, the effects they have on glomerular mesangial and podocyte cells and the tubulointerstitium, and how these contribute to driving fibrotic changes in the disease. CTGF can bind to several other growth factors modifying their function. CTGF is also able to interact with receptors on cells, including integrins, tyrosine receptor kinase A (TrkA), low density lipoprotein receptor-related protein (LRP) and heparan sulphate proteoglycans. These interactions, the intracellular signalling pathways they activate, and the cellular responses evoked are reviewed. CTGF also induces the expression of chemokines which themselves have pharmacological actions on cells. CTGF may prompt some responses by acting through several different mechanisms, possibly simultaneously. For example, CTGF is often described as an effector of TGF-β. It can promote TGF-β signalling by binding directly to the growth factor, promoting its interaction with the TGF-β receptor; by triggering intracellular signalling on binding the TrkA receptor, which leads to the transcriptional repression of Smad7, an inhibitor of the TGF-β signalling pathway; and by binding to BMP-7 whose own signalling pathway opposing TGF-β is inhibited, leading to enhanced TGF-β signalling

TNFa/TNFR2 signaling is required for glial ensheathment at the dorsal root entry zone

Somatosensory information from the periphery is routed to the spinal cord through centrally-projecting sensory axons that cross into the central nervous system (CNS) via the dorsal root entry zone (DREZ). The glial cells that ensheath these axons ensure rapid propagation of this information. Despite the importance of this glial-axon arrangement, how this afferent nerve is assembled during development is unknown. Using in vivo, time-lapse imaging we show that as centrally-projecting pioneer axons from dorsal root ganglia (DRG) enter the spinal cord, they initiate expression of the cytokine TNFalpha. This induction coincides with ensheathment of these axons by associated glia via a TNF receptor 2 (TNFR2)-mediated process. This work identifies a signaling cascade that mediates peripheral glial-axon interactions and it functions to ensure that DRG afferent projections are ensheathed after pioneer axons complete their navigation, which promotes efficient somatosensory neural function

Quantifying Geographic Variation in the Climatic Drivers of Midcontinent Wetlands with a Spatially Varying Coefficient Model

The wetlands in the Prairie Pothole Region and in the Great Plains are notorious for their sensitivity to weather variability. These wetlands have been the focus of considerable attention because of their ecological importance and because of the expected impact of climate change. Few models in the literature, however, take into account spatial variation in the importance of wetland drivers. This is surprising given the importance spatial heterogeneity in geomorphology and climatic conditions have in the region. In this paper, I use spatially-varying coefficients to assess the variation in ecological drivers in a number of ponds observed over a 50-year period (1961-2012). I included the number of ponds observed the year before on a log scale, the log of total precipitation, and mean maximum temperature during the four previous seasons as explanatory variables. I also included a temporal component to capture change in the number of ponds due to anthropogenic disturbance. Overall, fall and spring precipitation were most important in pond abundance in the west, whereas winter and summer precipitation were the most important drivers in the east. The ponds in the east of the survey area were also more dependent on pond abundance during the previous year than those in the west. Spring temperature during the previous season influenced pond abundance; while the temperature during the other seasons had a limited effect. The ponds in the southwestern part of the survey area have been increasing independently of climatic conditions, whereas the ponds in the northeast have been steadily declining. My results underline the importance of accounting the spatial heterogeneity in environmental drivers, when working at large spatial scales. In light of my results, I also argue that assessing the impacts of climate change on wetland abundance in the spring, without more accurate climatic forecasting, will be difficult

Stream power as a predictor of aquatic macroinvertebrate assemblages in the Yarlung Tsangpo River Basin (Tibetan Plateau)

Assemblage structures and distribution patterns of aquatic macroinvertebrates are influenced by riverine environmental variables. The relationship between environmental variables and macroinvertebrate assemblages, however, has rarely been examined quantitatively for rivers with high stream power at high altitude. In this study, stream power was analyzed in relation to macroinvertebrate distributions in the Yarlung Tsangpo River Basin on the Tibetan Plateau. Field investigations were carried out at 22 sites in April, 2014 and 2015. Stream power, substrate size and evenness, discharge, bedload transport, and organic detritus availability varied greatly among these sites. In total, 125 taxa of macroinvertebrates belonging to 48 families and 104 genera were identified. The macroinvertebrate density was negatively and significantly correlated with the stream power (D = 3.30, P < 0.001). Both the assemblage indices (taxa richness, density, biomass, and the Improved Shannon–Wiener Index) and the environmental variables (elevation, substrate size, and discharge) differed among the sites with different levels of stream power. An adaptability analysis showed contrasting adaptive strengths of typical taxa. Orthocladius, Baetis, and Simulium adapted to wide ranges of stream power and their most optimal stream powers were relatively high, while Bethbilbeckia and Natarsia were only well-adapted to fairly narrow ranges in stream power. Some macroinvertebrates have evolved specific strategies to adapt to high stream power: Baetidae and Heptageniidae have developed specialized body shapes, and Epoicocladius has altered its host preference. The stream power has been shown to be significantly correlated with and could be used to predict macroinvertebrate density in the Yarlung Tsangpo River Basin.No Full Tex