Autocrine loops with positive feedback enable context-dependent cell signaling

We describe a mechanism for context-dependent cell signaling mediated by autocrine loops with positive feedback. We demonstrate that the composition of the extracellular medium can critically influence the intracellular signaling dynamics induced by extracellular stimuli. Specifically, in the epidermal growth factor receptor (EGFR) system, amplitude and duration of mitogen-activated protein kinase (MAPK) activation are modulated by the positive-feedback loop formed by the EGFR, the Ras-MAPK signaling pathway, and a ligand-releasing protease. The signaling response to a transient input is short-lived when most of the released ligand is lost to the cellular microenvironment by diffusion and/or interaction with an extracellular ligand-binding component. In contrast, the response is prolonged or persistent in a cell that is efficient in recapturing the endogenous ligand. To study functional capabilities of autocrine loops, we have developed a mathematical model that accounts for ligand release, transport, binding, and intracellular signaling. We find that context-dependent signaling arises as a result of dynamic interaction between the parts of an autocrine loop. Using the model, we can directly interpret experimental observations on context-dependent responses of autocrine cells to ionizing radiation. In human carcinoma cells, MAPK signaling patterns induced by a short pulse of ionizing radiation can be transient or sustained, depending on cell type and composition of the extracellular medium. On the basis of our model, we propose that autocrine loops in this, and potentially other, growth factor and cytokine systems may serve as modules for context-dependent cell signaling.     

Neural mechanisms of alarm pheromone signaling

Alarm pheromones are important semiochemicals used by many animal species to alert conspecifics or other related species of impending danger. In this review, we describe recent developments in our understanding of the neural mechanisms underlying the ability of fruit flies, zebrafish and mice to mediate the detection of alarm pheromones. Specifically, alarm pheromones are detected in these species through specialized olfactory subsystems that are unique to the chemosensitive receptors, second messenger-signaling and physiology. Thus, the alarm pheromones appears to be detected by signaling mechanisms that are distinct from those seen in the canonical olfactory system.     

Regulation of pollen tube polarity: Feedback loops rule

Targeted delivery of immotile sperm through growing pollen tubes is a crucial step in achieving sexual reproduction in angiosperms. Unlike diffuse-growing cells, the growth of a pollen tube is restricted to the very apical region where targeted exocytosis and regulated endocytosis occur. The plant-specific Rho GTPases, Rops, are central organizers for pollen tube polarity. Through effector binding, Rops regulate the tip-focused Ca²⁺ gradient and the actin cytoskeleton during pollen tube growth. Therefore, understanding the spatiotemporal regulation of Rop activity would reveal how establishment and maintenance of tube polarity as well as re-orientation of the growth axis are accomplished. Recent findings indicated that two feedback loops may be fundamental in maintaining a fine-tuned and dynamic Rop activity. The concerted activities of RopGAP and RopGDI prevent lateral diffusion of activated Rop, restricting Rop activity to the apical plasma membrane. Conversely, pollen receptor kinases (PRKs) and RopGEFs positively feedback regulate Rop activity through protein binding and membrane recruitment. Feedback loops would also be essential for pollen tube re-orientation. Shallow extracellular cues amplified by concerted activities of feedback loops would lead to asymmetric activation of Rop and result in tube re-orientation.Key words: Rho GTPases, Rop, GEF, GAP, GDI, receptor kinase, feedback loop     

A possible link between parasite defence and residual reproduction

Life-history theory centres around trade-offs between current and future reproduction, but we have little understanding of how such trade-offs are mediated. We supplementary fed Ural owls (Strix uralensis) during the nestling period and quantified parents' current and future life-history components as well as their physiological health by monitoring haematocrit, leucocyte profile, intra- and extracellular blood parasites. Feeding led to reduced parental effort but did not improve offspring viability, male parasite defence, or parental survival. Intracellular leucocytozoan infection was reduced in fed females which lasted to the following year's reproductive season (carry-over effect), when fed females also laid larger and earlier clutches. Leucocytozoon infection therefore may mediate the life-history trade-off between current and residual reproduction in this species.     

Feedback loops between 3D vegetation structure and ecological functions of animals

Ecosystems function in a series of feedback loops that can change or maintain vegetation structure. Vegetation structure influences the ecological niche space available to animals, shaping many aspects of behaviour and reproduction. In turn, animals perform ecological functions that shape vegetation structure. However, most studies concerning three-dimensional vegetation structure and animal ecology consider only a single direction of this relationship. Here, we review these separate lines of research and integrate them into a unified concept that describes a feedback mechanism. We also show how remote sensing and animal tracking technologies are now available at the global scale to describe feedback loops and their consequences for ecosystem functioning. An improved understanding of how animals interact with vegetation structure in feedback loops is needed to conserve ecosystems that face major disruptions in response to climate and land-use change.     

Redox signaling loops in the unfolded protein response

The endoplasmic reticulum (ER) is the first compartment of secretory pathway. It plays a major role in ER chaperone-assisted folding and quality control, including post-translational modification such as disulfide bond formation of newly synthesized secretory proteins. Protein folding and assembly takes place in the ER, where redox conditions are distinctively different from the other organelles and are favorable for disulfide formation. These reactions generate the production of reactive oxygen species (ROS) as a byproduct of thiol/disulfide exchange reaction among ER oxidoreductin 1 (Ero1), protein disulfide isomerase (PDI) and ER client proteins, during the formation of disulfide bonds in nascent or incorrectly folded proteins. When uncontrolled, this phenomenon perturbs ER homeostasis, thus aggravating the accumulation of improperly folded or unfolded proteins in this compartment (ER stress). This results in the activation of an adaptive mechanism named the unfolded protein response (UPR). In mammalian cells, the UPR is mediated by three ER-resident membrane proteins (PERK, IRE1 and ATF6) and regulates the expression of the UPR target genes, which themselves encode ER chaperones, folding enzymes, pro-apoptotic proteins and antioxidants, with the objective of restoring ER homeostatic balance. In this review, we will describe redox dependent activation (ER) and amplification (cytosol) loops that control the UPR and the consequences these regulatory loops have on cell fate and physiology.     

Long-range functional loops in the mouse olfactory system and their roles in computing odor identity

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Increased behavioral and neuronal sensitivity to sex pheromone after brief odor experience in a moth

Plasticity in the response to stimuli related to food and oviposition cues is well documented in insects. However, responses to cues related to reproduction, for example, sex pheromones, are considered to be innate and thus not affected by experience. Here we show that brief preexposure to sex pheromones, without ensuing reward, lowers the threshold for behavioral response and augments the sensitivity in antennal lobe interneurons to pheromone compared with naive male moths. Thus, the sex pheromone system in insects can be modulated by experience. In addition, we show that the behavioral attraction to sex pheromone increases after preexposure in a time-dependent manner: a short-term effect, possibly a form of sensitization, and a long-term effect after more than 24 h. The behavioral long-term effect is paralleled by an increase in sensitivity of interneurons in the primary olfactory center, whereas the peripheral olfactory system does not change its sensitivity. We hypothesize that short-term sensitization to sex pheromone serves as a kind of alert system, whereas the long-term effect improves male performance when reproductively active females are present.     

Feedback regulation of EGFR signalling: decision making by early and delayed loops

Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks - such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.     

Manipulating insulin signaling to enhance mosquito reproduction

Backgrond  

In the mosquito Aedes aegypti the insulin/insulin growth factor I signaling (IIS) cascade is a key regulator of many physiological processes, including reproduction. Two important reproductive events, steroidogenesis in the ovary and yolk synthesis in the fat body, are regulated by the IIS cascade in mosquitoes. The signaling molecule phosphatase and tensin homolog (PTEN) is a key inhibitor of the IIS cascade that helps modulate the activity of the IIS cascade. In Ae. aegypti, six unique splice variants of AaegPTEN were previously identified, but the role of these splice variants, particularly AaegPTEN3 and 6, were unknown.     

Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops

BACKGROUND: Growth factors and their receptor tyrosine kinases play pivotal roles in development, normal physiology, and pathology. Signal transduction is regulated primarily by receptor endocytosis and degradation in lysosomes ("receptor downregulation"). c-Cbl is an adaptor that modulates this process by recruiting binding partners, such as ubiquitin-conjugating enzymes. The role of another group of adaptors, Sprouty proteins, is less understood; although, studies in insects implicated the founder protein in the negative regulation of several receptor tyrosine kinases. RESULTS: By utilizing transfection of living cells, as well as reconstituted in vitro systems, we identified a dual regulatory mechanism that combines human Sprouty2 and c-Cbl. Upon activation of the receptor for the epidermal growth factor (EGFR), Sprouty2 undergoes phosphorylation at a conserved tyrosine that recruits the Src homology 2 domain of c-Cbl. Subsequently, the flanking RING finger of c-Cbl mediates poly-ubiquitination of Sprouty2, which is followed by proteasomal degradation. Because phosphorylated Sprouty2 sequesters active c-Cbl molecules, it impedes receptor ubiquitination, downregulation, and degradation in lysosomes. This competitive interplay occurs in endosomes, and it regulates the amplitude and longevity of intracellular signals. CONCLUSIONS: Sprouty2 emerges as an inducible antagonist of c-Cbl, and together they set a time window for receptor activation. When incorporated in signaling networks, the coupling of positive (Sprouty) to negative (Cbl) feedback loops can greatly enhance output diversification.