Protein phosphatase modulation of the intercellular junctional communication: importance in cardiac myocytes

The rhythmic contraction of a four-chambered heart is a highly co-ordinated process, requiring the sequential activation of pacemaker cells and the propagation of activity throughout the whole myocardium. Gap-junctional channels, providing enclosed conduits for direct cell-to-cell transfer of ions and small molecules between adjacent cells, allow depolarising currents to flow from excited to non-excited regions of the network and a gradual spreading of the action potential. Gap-junctional channels are dodecamers of transmembrane proteins belonging in chordates to the connexin (Cx) family. In mammalian hearts, cardiomyocytes most prominently express junctional channels built of three Cxs: Cx40, Cx43 and Cx45. As with the great majority of Cx, they are phosphoproteins and exist under different phosphorylated levels. Phosphorylation, a widespread post-translational modification of proteins, is a primary means of mediating signal transduction events that control numerous cellular processes via a highly regulated dynamic interplay of protein kinases (PKs) and protein phosphatases (PPs). These processes appear implicated in the regulation of gap-junctional communication at several stages of the Cx lifecycle, including intracellular Cx trafficking, connexon assembly and disassembly, Cx degradation as well as the gating of gap-junction channels, but the underlying mechanisms remain poorly understood. Although PKs have an established role in this process, less is known about the involvement of PPs. The present review examines the roles played by protein dephosphorylation catalysers in the regulation of the gap-junctional communication in general, with a special focus on the junctional communication between cardiac cells.     

Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment

Inappropriate chemokine/receptor expression or regulation is linked to many diseases, especially those characterized by an excessive cellular infiltrate, such as rheumatoid arthritis and other inflammatory disorders. There is now overwhelming evidence that chemokines are also involved in the progression of cancer, where they function in several capacities. First, specific chemokine-receptor pairs are involved in tumour metastasis. This is not surprising, in view of their role as chemoattractants in cell migration. Secondly, chemokines help to shape the tumour microenvironment, often in favour of tumour growth and metastasis, by recruitment of leucocytes and activation of pro-inflammatory mediators. Emerging evidence suggests that chemokine receptor signalling also contributes to survival and proliferation, which may be particularly important for metastasized cells to adapt to foreign environments. However, there is considerable diversity and complexity in the chemokine network, both at the chemokine/receptor level and in the downstream signalling pathways they couple into, which may be key to a better understanding of how and why particular chemokines contribute to cancer growth and metastasis. Further investigation into these areas may identify targets that, if inhibited, could render cancer cells more susceptible to chemotherapy.     

Studies on coexistence and intercellular communication

Mouse ascites tumor cells (MAT-cells) were co-cultured with mesothelial cells of the mouse. During early stages of coexistence (30–60 min) the mesothelial cells show finger-like protrusions formed mostly at their flanks pointing towards MAT-cells in the neighbourhood. Obviously there is a directional response of the mesothelial cells to the existence of MAT-cells. The mesothelial cells are the more active partner at the beginning of coexistence. Later on MAT-cells also develop fingerlike protrusions which grow towards the mesothelial cells. A network of fingerlike protrusions is formed in the region between MAT-cells and mesothelial cells when they come near to each other. The advantages of the system serving as a model for investigations on intercellular communication are discussed.     

Effects of garlic oil on tumoragenecity and intercellular communication in human gastric cancer cell line

Previous studies have demonstrated that garlic oil (GO) and its anti-tumor compound could inhibit DNA and RNA synthesis in human cancer cells.In order to explore the effects of garlic oil on carcinoma cells,a gastric carcinoma cell line,BGC-823 was studied at cellular and molecular levels after garlic oil treatment.Data showed that the cell differentiation and suppression of tumorigenicity were significantly induced in tumor cells after garlic oil treatment.There was a correlation between the cell-cell communication recovery and the increase of p53 and waf1/p21 gene expression in garlic oil-treated cells.This result suggested that tumor suppressor gene waf1/p21 and wt p53 might play an important role in this effect.     

Effects of garlic oil on tumoragenecity and intercellular communication in human gastric cancer cell line

Previous studies have demonstrated that garlic oil (GO) and its anti-tumor compound could inhibit DNA and RNA synthesis in human cancer cells. In order to explore the effects of garlic oil on carcinoma cells, a gastric carcinoma cell line, BGC-823 was studied at cellular and molecular levels after garlic oil treatment. Data showed that the cell differentiation and suppression of tumorigenicity were significantly induced in tumor cells after garlic oil treatment. There was a correlation between the cell-cell communication recovery and the increase of p53 and waf1/p21 gene expression in garlic oil-treated cells. This result suggested that tumor suppressor gene waf1/p21 and wt p53 might play an important role in this effect.     

Follicle formation in the embryonic chick thyroid. III. Initiation of follicle formation

It has been proposed that the follicular spaces in the thyroid form by either the coalescence of intracellular droplets or by separation of cell apices by secretion into the extracellular space. On the basis of examination of thyroid primordia in early chick embryos this study provides evidence that in the chick, at least, follicle formation conforms to the second model. The first indications of change in the chick thyroid is the appearance of interdigitations of the cell apices. These interdigitations form microvilli as the two surfaces become separated and the follicular space is established. Vesicles with two types of contents can be identified in proximity with the cell surface during follicle formation, but it is not clear if either the dense particulate or the more electron-lucid materials that they contain actually enter the follicular space. Neither removal of the pituitary gland by decapitation nor inhibition of collagen synthesis and a concomitant failure of the invasion of capsular mesenchyme prevents the initiation of normal follicle formation.     

Exosomes: Extracellular organelles important in intercellular communication

In addition to intracellular organelles, eukaryotic cells also contain extracellular organelles that are released, or shed, into the microenvironment. These membranous extracellular organelles include exosomes, shedding microvesicles (SMVs) and apoptotic blebs (ABs), many of which exhibit pleiotropic biological functions. Because extracellular organelle terminology is often confounding, with many preparations reported in the literature being mixtures of extracellular vesicles, there is a growing need to clarify nomenclature and to improve purification strategies in order to discriminate the biochemical and functional activities of these moieties. Exosomes are formed by the inward budding of multivesicular bodies (MVBs) and are released from the cell into the microenvironment following the fusion of MVBs with the plasma membrane (PM). In this review we focus on various strategies for purifying exosomes and discuss their biophysical and biochemical properties. An update on proteomic analysis of exosomes from various cell types and body fluids is provided and host-cell specific proteomic signatures are also discussed. Because the ectodomain of ~ 42% of exosomal integral membrane proteins are also found in the secretome, these vesicles provide a potential source of serum-based membrane protein biomarkers that are reflective of the host cell. ExoCarta, an exosomal protein and RNA database (http://exocarta.ludwig.edu.au), is described.     

Exosomes: small vesicles participating in intercellular communication

Exosomes are small membrane vesicles, which eukaryotic cells secrete into their extracellular environment. They are formed as intraluminal vesicles by inward budding of the limiting membrane into the lumen of late endosomes. Upon fusion of thus arising multivesicular bodies with the plasma membrane, these vesicles are released as exosomes and enter body fluids such as blood plasma, urine and saliva. Containing certain combinations of lipids, adhesion and intercellular signaling molecules as well as RNAs, exosomes participate in intercellular communication processes. Depending on their origin, exosomes can modulate immune-regulatory processes, set up tumor escape mechanisms and mediate regenerative or degenerative processes, amongst others. In summary, exosomes are molecular complex intercellular signaling organelles with multiple functions, which appear as promising new tools for the clinical diagnostics and potentially for novel therapeutic strategies.     

Chemical communication in proteobacteria: biochemical and structural studies of signal synthases and receptors required for intercellular signalling

Cell-cell communication via the production and detection of chemical signal molecules has been the focus of a great deal of research over the past decade. One class of chemical signals widely used by proteobacteria consists of N-acyl-homoserine lactones, which are synthesized by proteins related to LuxI of Vibrio fischeri and are detected by proteins related to the V. fischeri LuxR protein. A related marine bacterium, Vibrio harveyi, communicates using two chemical signals, one of which, autoinducer-2 (AI-2), is a furanone borate diester that is synthesized by the LuxS protein and detected by a periplasmic protein called LuxP. Evidence from a number of laboratories suggests that AI-2 may be used as a signal by diverse groups of bacteria, and might permit intergeneric signalling. These two families of signalling systems have been studied from the perspectives of physiology, ecology, biochemistry, and more recently, structural biology. Here, we review the biochemistry and structural biology of both acyl-homoserine-lactone-dependent and AI-2-dependent signalling systems.     

Colonial organization and intercellular communication in microorganisms

This review covers the modern concepts and recent data demonstrating the integrity and coherence of microbial populations (colonies, biofilms, etc.) as peculiar “superorganisms.” Special attention is given to such relevant phenomena as apoptosis, bacterial altruism, quorum effects, collective differentiation of microbial cells, and the formation of population-level structures such as an extracellular matrix. Emphasis is placed on the channels and agents of intercellular communication in microbial populations. The involvement of a large number of evolutionarily conserved communicational facilities and patterns of intercellular interactions is underscored. Much attention is also given to the role of colonial organization and intercellular communication in parasite/commensal/symbiont-multicellular host organism systems.     

Gap junction-mediated intercellular communication in the immune system

Immune cells are usually considered non-attached blood cells, which would exclude the formation of gap junctions. This is a misconception since many immune cells express connexin 43 (Cx43) and other connexins and are often residing in tissue. The role of gap junctions is largely ignored by immunologists as is the immune system in the field of gap junction research. Here, the current knowledge of the distribution of connexins and the function of gap junctions in the immune system is discussed. Gap junctions appear to play many roles in antibody productions and specific immune responses and may be important in sensing danger in tissue by the immune system. Gap junctions not only transfer electrical and metabolical but also immunological information in the form of peptides for a process called cross-presentation. This is essential for proper immune responses to viruses and possibly tumours. Until now only 40 research papers on gap junctions in the immune system appeared and this will almost certainly expand with the increased mutual interest between the fields of immunology and gap junction research.