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.     

Coupled positive and negative feedback circuits form an essential building block of cellular signaling pathways

Cellular circuits have positive and negative feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such feedback loops exist in many cases in a particular form of coupled positive and negative feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled feedback circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn off the reaction when the stimulus disappears. In other words, coupled feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative feedback loops form essential signal transduction motifs in cellular signaling systems.     

Roles of positive and negative feedback in biological systems

We discuss the influence of positive and negative feedback on the stability of a system, which is not clear-cut, and involves complex, mathematical problems. We show in particular that positive feedback can have a stabilising effect on some systems. We also point out the role that positive feedback plays in the digital treatment of signals required by cellular signalling, drawing on analogies from electronics, and the role that negative feedback plays in making a system robust against alteration of its parameters. Both positive and negative feedback can be seen as important enhancers of the properties of biological systems.     

TGF-beta signaling: positive and negative effects on tumorigenesis.

TGF-beta binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-beta pathway from tumor suppressor to oncogene during tumorigenesis.     

Multiple positive and negative regulators of signaling by the EGF-receptor

Signaling via the epidermal growth factor (EGF)-receptor family is subject to regulation and modulation by multiple ligands, effectors and negative regulators, as well as regulation by heterodimerization between family members and crosstalk between heterologous signaling pathways. Besides serving as a paradigm for receptor tyrosine kinases in general, this family is crucial for development and is often mutated or amplified in human tumors.     

Differential effects of aging on estrogen negative and positive feedback

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.     

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.     

Maturation of negative and positive estrogen feedback in the prepubertal female rat

The development of estrogen feedback system on gonadotropin release during sexual maturation in female rats was studied. Animals (Wistar strain rats) were divided into 6 groups according to their ages; 10, 15, 20, 25, 30, and 35 days. Both LH and FSH levels in serum increased significantly in response to ovariectomy in all age-groups studied when measured one week postoperatively, though in the rats aged 10-15 days the increase in FSH following castration was only slight. In rats older than 25 days, the postcastration gonadotropin rise, calculated as a percent increase from the basal figure, decreased gradually with increasing age. Ovariectomized rats injected with estradiol benzoate (EB, 5 micrograms/100 g BW) showed significantly lower levels of both LH and FSH than those in castrated controls. However, the inhibitory action of EB on postcastration gonadotropin output was found to be relatively less effective in rats older than 25 days. Ovariectomized rats primed with EB were again injected with a 2nd dose of EB (5 micrograms/100 g BW) at noon 3 days after priming. The 2nd EB injection induced a significant rise in LH 6 h later in 30- and 35-day-old, though not in younger, animals. On the other hand, the FSH response to EB was markedly enhanced during days 15-25 of age. These results indicate that the estrogen negative feedback action on gonadotropin release is already operating in female rats at a very early age, and that the brain sensitivity to estrogen decreases slightly during the late prepubertal phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthetic robust perfect adaptation achieved by negative feedback coupling with linear weak positive feedback

Unlike their natural counterparts, synthetic genetic circuits are usually fragile in the face of environmental perturbations and genetic mutations. Several theoretical robust genetic circuits have been designed, but their performance under real-world conditions has not yet been carefully evaluated. Here, we designed and synthesized a new robust perfect adaptation circuit composed of two-node negative feedback coupling with linear positive feedback on the buffer node. As a key feature, the linear positive feedback was fine-tuned to evaluate its necessity. We found that the desired function was robustly achieved when genetic parameters were varied by systematically perturbing all interacting parts within the topology, and the necessity of the completeness of the topological structures was evaluated by destroying key circuit features. Furthermore, different environmental perturbances were imposed onto the circuit by changing growth rates, carbon metabolic strategies and even chassis cells, and the designed perfect adaptation function was still achieved under all conditions. The successful design of a robust perfect adaptation circuit indicated that the top-down design strategy is capable of predictably guiding bottom-up engineering for robust genetic circuits. This robust adaptation circuit could be integrated as a motif into more complex circuits to robustly implement more sophisticated and critical biological functions.     

土壤呼吸的温度敏感性——全球变暖正负反馈的不确定因素

基于模型模拟结果表明,全球变暖与大气CO2浓度增加将形成正反馈关系,这种正反馈效应将明显加速21世纪的气候变暖。然而,这些模拟模型都基于一个重要假设,即不同平均驻留时间的土壤有机质分解具有相同的温度敏感性(Q10)。这一假设与酶动力学理论相悖,而且不同学者对不同质量土壤有机质分解温度敏感性的差异的认识存在严重分歧,所以,全球变暖与大气CO2浓度增加的正反馈关系的显著性仍值得商榷。围绕土壤呼吸的温度敏感性问题进行了讨论和评述,涉及1)土壤有机质分解温度敏感性争论的焦点问题;2)通过经验模型曲线拟合估计Q10值存在的分歧及Q10变异的机理解释;3)实验室土壤培养实验估计Q10值存在的问题;4)土壤培养实验中Q10值计算方法的改进。进一步深化有关土壤有机质分解温度敏感性不确定性的认识,将为今后土壤呼吸及其对气候变化响应的相关研究提供参考。     

A comparison of resonance tuning with positive versus negative sensory feedback

We used a computational model of rhythmic movement to analyze how the connectivity of sensory feedback affects the tuning of a closed-loop neuromechanical system to the mechanical resonant frequency (ω_r). Our model includes a Matsuoka half-center oscillator for a central pattern generator (CPG) and a linear, one-degree-of-freedom system for a mechanical component. Using both an open-loop frequency response analysis and closed-loop simulations, we compared resonance tuning with four different feedback configurations as the mechanical resonant frequency, feedback gain, and mechanical damping varied. The feedback configurations consisted of two negative and two positive feedback connectivity schemes. We found that with negative feedback, resonance tuning predominantly occurred when ω_r was higher than the CPG’s endogenous frequency (ω_CPG). In contrast, with the two positive feedback configurations, resonance tuning only occurred if ω_r was lower than ω_CPG. Moreover, the differences in resonance tuning between the two positive (negative) feedback configurations increased with increasing feedback gain and with decreasing mechanical damping. Our results indicate that resonance tuning can be achieved with positive feedback. Furthermore, we have shown that the feedback configuration affects the parameter space over which the endogenous frequency of the CPG or resonant frequency the mechanical dynamics dominates the frequency of a rhythmic movement.     

Brain activity elicited by positive and negative feedback in preschool-aged children

To investigate the processing of positive vs. negative feedback in children aged 4-5 years, we devised a prize-guessing game that is analogous to gambling tasks used to measure feedback-related brain responses in adult studies. Unlike adult studies, the feedback-related negativity (FRN) elicited by positive feedback was as large as that elicited by negative feedback, suggesting that the neural system underlying the FRN may not process feedback valence in early childhood. In addition, positive feedback, compared with negative feedback, evoked a larger P1 over the occipital scalp area and a larger positive slow wave (PSW) over the right central-parietal scalp area. We believe that the PSW is related to emotional arousal and the intensive focus on positive feedback that is present in the preschool and early school years has adaptive significance for both cognitive and emotional development during this period.     

Modeling the hypothalamus–pituitary–adrenal system: homeostasis by interacting positive and negative feedback

The hypothalamus–pituitary–adrenal (HPA) system is closely related to stress and the restoration of homeostasis. This system is stimulated in the second half of the night, decreases its activity in the daytime, and reaches the homeostatic level during the late evening. In this paper, we derive and discuss a novel model for the HPA system. It is based on three simple rules that constitute a principle of homeostasis and include only the most substantive physiological elements. In contrast to other models, its main components include, apart from the conventional negative feedback ingredient, a positive feedback loop. To validate the model, we present a parameter estimation procedure that enables one to adapt the model to clinical observations. Using this methodology, we are able to show that the novel model is capable of simulating clinical trials. Furthermore, the stationary state of the system is investigated. We show that, under mild conditions, the system always has a well-defined set-point, which reflects the clinical situation to be modeled. Finally, the computed parameters may be interpreted from a physiological point of view, thereby leading to insights about diseases like depression, obesity, or diabetes.     

The p38 pathway provides negative feedback for Ras proliferative signaling

Ras activates three mitogen-activated protein kinases (MAPKs) including ERK, JNK, and p38. Whereas the essential roles of ERK and JNK in Ras signaling has been established, the contribution of p38 remains unclear. Here we demonstrate that the p38 pathway functions as a negative regulator of Ras proliferative signaling via a feedback mechanism. Oncogenic Ras activated p38 and two p38-activated protein kinases, MAPK-activated protein kinase 2 (MK2) and p38-related/activated protein kinase (PRAK). MK2 and PRAK in turn suppressed Ras-induced gene expression and cell proliferation, whereas two mutant PRAKs, unresponsive to Ras, had little effect. Moreover, the constitutive p38 activator MKK6 also suppressed Ras activity in a p38-dependent manner whereas arsenite, a potent chemical inducer of p38, inhibited proliferation only in a tumor cell line that required Ras activity. MEK was required for Ras stimulation of the p38 pathway. The p38 pathway inhibited Ras activity by blocking activation of JNK, without effect upon ERK, as evidenced by the fact that PRAK-mediated suppression of Ras-induced cell proliferation was reversed by coexpression of JNKK2 or JNK1. These studies thus establish a negative feedback mechanism by which Ras proliferative activity is regulated via signaling integrations of MAPK pathways.     

Microscopic spiral waves reveal positive feedback in subcellular calcium signaling.

The regenerative Ca(2+)-induced Ca2+ release mechanism is an important amplifier of signal transduction in diverse cells. In heart muscle cells, this mechanism contributes to the Ca2+ transient activating the mechanical contraction, but it is also believed to drive Ca2+ waves propagating within the cytosol. We investigated the subcellular Ca2+ distribution in heart muscle cells during spontaneous Ca2+ release using laser scanning confocal microscopy with a ratiometric fluorescent indicator technique. Besides planar Ca2+ waves with linear propagation, sequences of confocal optical sections also revealed spiral Ca2+ waves spinning around a subcellular core at approximately 1 Hz. Although the Ca2+ spirals were continuous processes they frequently exhibited an apparently oscillatory output function into the elongated cell body. These oscillatory waves emanating from the spiral at regular intervals were formally considered to be short outer segments of the spiral but could not be distinguished from planar Ca2+ waves propagating along the longitudinal cell axis. The complex spatiotemporal pattern of spiral Ca2+ waves implies the participation of an active process exhibiting a large degree of positive feedback, most likely the Ca(2+)-induced Ca2+ release mechanism.     

Type IV collagens and Dpp positive and negative regulators of signaling

Decapentaplegic (Dpp) is an essential morphogen in the TGF-β/BMP superfamily which patterns fields of cells during multiple stages of Drosophila development, including the ovary and embryo. We have found that type IV collagens bind to Dpp and play essential roles in the regulation of its signaling during these two developmental stages. This article primarily focuses on type IV collagens and embryonic Dpp signaling to discuss aspects of the type IV collagen mutant phenotype in the context of additional data from the field. In addition, the restriction of Dpp signaling in the the ovary by type IV collagens is described, as the differences between the embryonic and ovarian Dpp sources result in distinct effects of collagen IV proteins in the two systems.