Intracellular signal transduction pathways that control pancreatic beta-cell proliferation.

This review focuses on the factors that regulate the proliferation of pancreatic islet beta-cells in vitro, and in particular on the intracellular pathways that convey the mitogenic signal into a proliferative response. Substances as diverse as nutrients, polypeptides, cytokines, adrenergic agents, lithium, phorbol esters and cyclic AMP analogs are all able to stimulate or inhibit beta-cell proliferation in a time- and concentration-dependent manner. The evidence for involvement of cyclic AMP, cyclic GMP, protein kinase C, inositol polyphosphates, GTP-binding proteins, polyamines and oncogenes is reviewed.     

Wnt signal transduction pathways

The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output. To date major signaling branches downstream of the Fz receptor have been identified including a canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway which can be further divided into the Planar Cell Polarity and the Wnt/Ca²⁺ pathways, and these branches are being actively dissected at the molecular and biochemical levels. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of these pathways in regulating key events during embryonic patterning and morphogenesis.     

Wnt signal transduction pathways

The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, cell polarity, neural patterning and organogenesis during embryonic development. The Wnts are secreted glycoproteins and comprise a large family of nineteen proteins in humans hinting to a daunting complexity of signaling regulation, function and biological output. To date major signaling branches downstream of the Fz receptor have been identified including a canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway which can be further divided into the Planar Cell Polarity and the Wnt/Ca²⁺ pathways, and these branches are being actively dissected at the molecular and biochemical levels. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of these pathways in regulating key events during embryonic patterning and morphogenesis.Key words: Wnt, frizzled, dishevelled, canonical, non-canonical, β-catenin, Planar Cell Polarity     

Investigation of signal transduction pathways involved in melanoma cell spreading

Integrins are a major family of heterodimeric adhesion receptors that are responsible for anchoring cells to extracellular matrix and they also can initiate intracellular signal pathways. Here parental and alpha 4-expressing human malignant melanoma cell lines were used to study the effect of protein kinase C (PKC), protein tyrosine kinases (PTKs) and intracellular Ca2+ on alpha 4 beta 1-mediated cell spreading on VCAM-1. Incubation of melanoma cells with PKC inhibitor inhibited alpha 4 beta 1-mediated melanoma cell spreading completely. Effect of intracellular Ca2+ on melanoma cell spreading was also investigated by non-phorbol ester tumor promotor, thapsigargin, which blocks the ability of the endoplasmic reticulum to replenish stocks of calcium which naturally leak out into the cytosol leading to a transient increase in concentration of intracellular calcium. The results showed that alpha 4 beta 1-mediated spreading was also required intracellular calcium involvement. However, in the presence of PTKs inhibitor melanoma cells showed long, thin dendiritic projections compared to control cells. Previously, data was obtained from immunofluorescense experiments showed that after genistein treatment, alpha 4-expressing cells exhibited considerable amounts of alpha 4 integrin and PTKs in both the focal contact points as well as over the whole cell. PTKs inhibitor did not have any effect on alpha 4-expressing cells spreading. This could be related to the amount of the PTKs present in these cells.     

Two-component signal transduction pathways in Arabidopsis

The two-component system, consisting of a histidine (His) protein kinase that senses a signal input and a response regulator that mediates the output, is an ancient and evolutionarily conserved signaling mechanism in prokaryotes and eukaryotes. The identification of 54 His protein kinases, His-containing phosphotransfer proteins, response regulators, and related proteins in Arabidopsis suggests an important role of two-component phosphorelay in plant signal transduction. Recent studies indicate that two-component elements are involved in plant hormone, stress, and light signaling. In this review, we present a genome analysis of the Arabidopsis two-component elements and summarize the major advances in our understanding of Arabidopsis two-component signaling.     

Integrin-mediated signal transduction pathways.

Integrins serve as adhesion receptors for extracellular matrix proteins and also transduce biochemical signals into the cell. They regulate a variety of cellular functions, including spreading, migration, proliferation and apoptosis. Many signaling pathways downstream of integrins have been identified and characterized and are discussed here. In particular, integrins regulate many protein tyrosine kinases and phosphatases, such as FAK and Src, to coordinate many of the cell processes mentioned above. The regulation of MAP kinases by integrins is important for cell growth or other functions, and the putative roles of Ras and FAK in these pathways are discussed. Phosphatidylinositol lipids and their modifying enzymes, particularly PI 3-kinase, are strongly implicated as mediators of integrin-regulated cytoskeletal changes and cell migration. Similarly, actin cytoskeleton regulation by the Rho family of GTPases is coordinated with integrin signaling to regulate cell spreading and migration, although the exact relationship between these pathways is not clear. Finally, intracellular pH and calcium fluxes by integrins are suggested to affect a variety of cellular proteins and functions.     

Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression.     

Knowledge representation of signal transduction pathways

MOTIVATIONS: Signal transduction is the common term used to define a diverse topic that encompasses a large body of knowledge about the biochemical mechanisms. Since most of the knowledge of signal transduction resides in scientific articles and is represented by texts in natural language or by diagrams, there is the need of a knowledge representation model for signal transduction pathways that can be as readily processed by a computer as it is easily understood by humans. RESULTS: A signal transduction pathway representation model is presented. It is based on a compound graph structure and is designed to handle the diversity and hierarchical structure of pathways. A prototype knowledge base was implemented on a deductive database and a number of biological queries are demonstrated on it.     

Power-law models of signal transduction pathways

The mathematical modelling of signal transduction pathways has become a valuable aid to understanding the complex interactions involved in intracellular signalling mechanisms. An important aspect of the mathematical modelling process is the selection of the model type and structure. Until recently, the convention has been to use a standard kinetic model, often with the Michaelis-Menten steady state assumption. However this model form, although valuable, is only one of a number of choices, and the aim of this article is to consider the mathematical structure and essential features of an alternative model form--the power-law model. Specifically, we analyse how power-law models can be applied to increase our understanding of signal transduction pathways when there may be limited prior information. We distinguish between two kinds of power law models: a) Detailed power-law models, as a tool for investigating pathways when the structure of protein-protein interactions is completely known, and; b) Simplified power-law models, for the analysis of systems with incomplete structural information or insufficient quantitative data for generating detailed models. If sufficient data of high quality are available, the advantage of detailed power-law models is that they are more realistic representations of non-homogenous or crowded cellular environments. The advantages of the simplified power-law model formulation are illustrated using some case studies in cell signalling. In particular, the investigation on the effects of signal inhibition and feedback loops and the validation of structural hypotheses are discussed.     

Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity

Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientation and microtubule polarization depend on a Cdc42-regulated signal transduction pathway involving activation of the Par6/aPKC complex followed by inhibition of GSK-3beta and accumulation of the adenomatous polyposis coli (APC) protein at the plus ends of leading-edge microtubules. Using monolayers of primary rodent embryo fibroblasts, we show here that dishevelled (Dvl) and axin, two major components of the Wnt signaling pathway are required for centrosome reorientation and that Wnt5a is required for activation of this pathway. We conclude that disruption of cell-cell contacts leads to the activation of a noncanonical Wnt/dishevelled signal transduction pathway that cooperates with Cdc42/Par6/aPKC to promote polarized reorganization of the microtubule cytoskeleton.     

Genetic and molecular analyses of mutations involved in Drosophila raf signal transduction.

We have identified dominant mutations that suppress the lethality associated with an R217-->L mutation in the GTP.Ras binding region (CR1) of the Drosophila raf (D-raf) serine/threonine kinase. Four intragenic and seven extragenic suppressors were recovered. Each of the four intragenic mutations contains one compensatory amino acid change located in either the CR1 or the kinase domain of D-raf. The seven extragenic suppressors represent at least four genetic loci whose effects strongly suggest that they participate in both the sevenless and Drosophila EGF receptor (DER) signaling pathways. One of these mutations, Su(D-raf)34B, is an allele of D-mek which encodes the known signaling molecule MAPK kinase (MEK). A D83V mutation in D-MEK is identified and shown to be sufficient to confer the dominant activity of Su(D-raf)34B.     

N-乙酰氨基葡萄糖化在信号转导中的作用

蛋白质磷酸化在生命活动以及信号转导过程中的重要作用已经被研究证实,但不少研究发现在大多数核,胞液蛋白质上不仅存在磷酸化动态修饰,还存在广泛的动态N－乙酰氨基葡萄糖修饰,N－乙酰氨基葡萄糖基转移酶和N－乙酰氨基葡萄糖基酶以类似于蛋白质激酶和磷酸酶的方式调节蛋白质是否发生N－乙酰氨基葡萄糖化。N－乙酰氨基葡萄糖化蛋白质主要分布在细胞核与胞液,其生理功能涉及细胞基本生命活动和调节信号传递。N－乙酰氨基葡萄糖的作用基础与阻断或影响蛋白质的磷酸化有关。     

Phytochrome and UV signal transduction pathways

The phytochromes are the best studied plant photoreceptors, controlling a wide variety of responses at both whole plant and single cell levels. Three signal transduction pathways, dependent on cGMP and/or calcium, have been found to be utilized by phytochrome to control the expression of genes required for chloroplast development (e.g., CAB and FNR) and anthocyanin biosynthesis (e.g., CHS). In particular, cGMP is a second messenger positively regulating CHS gene expression whilst calcium and calmodulin act as negative regulators. In addition to phytochrome regulation of CHS we have begun to examine the signal transduction pathways utilized by UV photoreceptors. In contrast to phytochrome-mediated responses, results indicate a role for calcium and calmodulin as positive regulators of CHS gene expression in UV light.     

Targeting prostate cancer based on signal transduction and cell cycle pathways

Prostate cancer remains a leading cause of death in men despite increased capacity to diagnose at earlier stages. After prostate cancer has become hormone independent, which often occurs after hormonal ablation therapies, it is difficult to effectively treat. Prostate cancer may arise from mutations and dysregulation of various genes involved in regulation signal transduction (e.g., PTEN, Akt, etc) and the cell cycle (e.g., p53, p21Cip1, p27Kip1, Rb, etc.). This review focuses on the aberrant interactions of signal transduction and cell cycle genes products and how they can contribute to prostate cancer and alter therapeutic effectiveness.