Identification of galectins as novel regulators of platelet signaling and function

Platelet activation at sites of vascular injury leads to the formation of a hemostatic plug. Activation of platelets is therefore crucial for normal hemostasis. However, uncontrolled platelet activation may also lead to the formation of occlusive thrombi that can cause ischemic events. Platelets can be activated by soluble molecules including thrombin, TXA2 , adenosine diphosphate (ADP), and serotonin or by adhesive extracellular matrix (ECM) proteins such as von Willebrand factor and collagen. In this article, we review recent advances on the role of galectins in platelet physiology. By acting in either soluble or immobilized form, these glycan-binding proteins trigger platelet activation through modulation of discrete signaling pathways. We also offer new hypotheses and some speculations about the role of platelet-galectin interactions not only in hemostasis and thrombosis but also in inflammation and related diseases such as atherosclerosis and cancer.     

Glycosylation in cellular mechanisms of health and disease

Glycosylation produces an abundant, diverse, and highly regulated repertoire of cellular glycans that are frequently attached to proteins and lipids. The past decade of research on glycan function has revealed that the enzymes responsible for glycosylation-the glycosyltransferases and glycosidases-are essential in the development and physiology of living organisms. Glycans participate in many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. This review discusses the increasingly sophisticated molecular mechanisms being discovered by which mammalian glycosylation governs physiology and contributes to disease.     

Bioinformatics and cellular signaling

The understanding of cellular function requires an integrated analysis of context-specific, spatiotemporal data from diverse sources. Recent advances in describing the genomic and proteomic 'parts list' of the cell and deciphering the interrelationship of these parts are described, including genome-wide location analysis, standards for microarray data analysis, and two-hybrid and mass spectrometry approaches. This information is being collected and curated in databases such as the Alliance for Cellular Signaling (AfCS) Molecule Pages, which will serve as vital tools for the reconstruction and analysis of cellular signaling networks.     

Simulating cellular galectin networks by mixing galectins in vitro reveals synergistic activity

BackgroundEven though members of the family of adhesion/growth-regulatory galectins are increasingly detected to be co-expressed, they are still being routinely tested separately. The recent discovery of heterodimer formation among galectins-1, -3, and -7 in mixtures prompts further study of their functional activities in mixtures.MethodsCell agglutination, galectin binding to cells, as well as effects on cell proliferation, onset of apoptosis and migration were determined in assays using various cell types and mixtures of galectins-1, -3, and -7.ResultsEvidence for a more than additive increases of experimental parameters was consistently obtained.ConclusionTesting galectins in mixtures simulates the situation of co-expression in situ and reveals unsuspected over-additive activities. This new insight is relevant for analyzing galectin functionality in (patho)physiological conditions.     

Cadherin-mediated cellular signaling

Recent cadherin studies focusing on cellular signaling have shown that several pathways are activated by cadherin-mediated cell-cell contact. Cadherin-mediated contacts activate Rho family GTPases, regulate the availability of beta-catenin to participate in Wnt signaling, and function in receptor tyrosine kinase signaling. Although different classical cadherins bind to the same cytosolic proteins via their cytoplasmic tails, one message that is clear from the recent literature is that downstream signals emanating from cadherin-mediated contacts are both cadherin-specific and cell-context-specific.     

Inflammatory signaling and cellular senescence

Inflammation acts as a double-edged sword in the pathogenesis of cancer. Inflammatory responses play a key role in eliminating potentially cancerous cells; however, an inflammatory microenvironment also promotes the development of cancer. Proinflammatory cytokines, the key mediators of inflammation, also play a dual role in oncogenesis. While they can promote neoplastic progression, recent studies have revealed an unexpected function of the inflammatory pathways in inhibiting cancer development. These studies demonstrate that cells undergoing senescence, a cellular program serving as a barrier to cancer development, produce increased amount of inflammatory cytokines. These inflammatory cytokines play an essential role in the initiation and maintenance of cellular senescence, and are responsible for triggering an innate immune response that clears the senescent tumor cells in vivo. The purpose of the present review is to discuss the dual roles of the inflammatory cytokines produced by senescent cells in the pathogenesis of cancer, and the signaling pathway mediating their role in cellular senescence.     

Calcium signaling and cellular senescence

Cellular senescence is a stable cell proliferation arrest induced by a variety of stresses including telomere shortening, oncogene activation and oxidative stress. This process plays a crucial role in many physiopathological contexts, especially during aging when cellular senescence favors development of age-related diseases, shortening lifespan. However, the molecular and cellular mechanisms controlling senescence are still a matter of active research. In the last decade, there has been emerging literature indicating a key involvement of calcium signaling in cellular senescence. In this review we will initially give an account of the direct evidence linking calcium and the regulation of senescence. We will then review our current knowledge on the role of calcium in some senescence-associated features and physiopathological conditions, which will shed light on additional ways in which calcium signaling is implicated in cellular senescence.     

Mammalian galectins: Structure,carbohydrate specificity,and functions

Galectins are a family of beta-galactoside binding lectins, homological by a sequence of the carbohydrate-binding site. In this review literature data about structure and carbohydrate specificity of galectins are discussed. The role of galectins in the regulation of cell adhesion in immune response, inflammation, and cancer progression is considered.     

Spotlight on cellular signaling

On May 21-27, 2004, the fourth in an ongoing series of Dubrovnik Conferences on Cellular Signaling was held at the beautiful Croatian resort of Cavtat, outside the historic town of Dubrovnik. The largest so far in the biannual series attracted an audience of over 300. A series of topics was discussed in depth. Here we concentrate on three areas: receptor tyrosine kinase signaling, actin rearrangements, and endocytosis.     

Introduction to galectins

Good evidence suggest roles of galectins in cancer, immunity and inflammation, and development, but a unifying picture of their biological function is lacking. Instead galectins appear to have a particularly diverse, bewildering but intriguing array of activities both inside and outside cells—“clear truths and mysteries are inextricably twined”. Fortunately this has not discouraged but rather enthused a large number of good galectin researchers, some of which have contributed to this special issue of Glycoconjugate Journal to provide a personal, critical status of the field. Here we will give a brief introduction to the galectins as a protein family with some comments on nomenclature. Published in 2004.     

Nitric oxide chemistry and cellular signaling

Nitric oxide (NO) has been shown to mediate a number of different physiological functions within every major organ system. This wide variety of functional roles is made all the more remarkable when one considers that NO is a simple diatomic molecule. However, despite the simplicity of the molecule, NO possesses a wide range of chemical reactivity and multiple potential reactive targets. It is the variability of NO reactivity, which leads to its capability to control such a vast range of biological functions. In essence the functionality of NO is controlled by its chemical reactivity. In order to understand this possibility further it is necessary to consider the biologically relevant reactions of nitric oxide.     

Introduction to galectins

Good evidence suggest roles of galectins in cancer, immunity and inflammation, and development, but a unifying picture of their biological function is lacking. Instead galectins appear to have a particularly diverse, bewildering but intriguing array of activities both inside and outside cells--"clear truths and mysteries are inextricably twined". Fortunately this has not discouraged but rather enthused a large number of good galectin researchers, some of which have contributed to this special issue of Glycoconjugate Journal to provide a personal, critical status of the field. Here we will give a brief introduction to the galectins as a protein family with some comments on nomenclature.     

Intracellular functions of galectins

Many galectin family members are detected primarily intracellularly in most of the systems studied, although certain members can be found both inside and outside of cells. Specific functions that are consistent with their intracellular localization have now been documented for some of the galectins. Galectin-1 and -3 have been identified as redundant pre-mRNA splicing factors. Galectin-3, -7, and -12 have been shown to regulate cell growth and apoptosis, being either anti-apoptotic or pro-apoptotic. Galectin-3 and -12 have been shown to regulate the cell cycle. In some cases, the mechanisms by which galectins exert their functions have been partially delineated in relation to known intracellular pathways associated with these processes. In addition, a number of intracellular proteins involved in these processes have been identified as the interacting ligands of certain galectins. This review summarizes the intracellular activities displayed by several galectins and discusses the possible underlying mechanisms.     

Proteomic analysis of cellular signaling

Protein phosphorylation events are key regulators of cellular signaling processes. In the era of functional genomics, rational drug design programs demand large-scale high-throughput analysis of signal transduction cascades. Significant improvements in the area of mass spectrometry-based proteomics have provided exciting opportunities for rapid progress toward global protein phosphorylation analysis. This review summarizes several recent advances made in the field of phosphoproteomics with an emphasis placed on mass spectrometry instrumentation, enrichment methods and quantification strategies. In the near future, these technologies will provide a tool that can be used for quantitative investigation of signal transduction pathways to generate new insights into biologic systems.     

Proteomic analysis of cellular signaling

Protein phosphorylation events are key regulators of cellular signaling processes. In the era of functional genomics, rational drug design programs demand large-scale high-throughput analysis of signal transduction cascades. Significant improvements in the area of mass spectrometry-based proteomics have provided exciting opportunities for rapid progress toward global protein phosphorylation analysis. This review summarizes several recent advances made in the field of phosphoproteomics with an emphasis placed on mass spectrometry instrumentation, enrichment methods and quantification strategies. In the near future, these technologies will provide a tool that can be used for quantitative investigation of signal transduction pathways to generate new insights into biologic systems.