Cells2014, 3(2), 304-330; doi:10.3390/cells3020304 - published online 22 April 2014 Show/Hide Abstract
Abstract: Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights.
Cells2014, 3(2), 288-303; doi:10.3390/cells3020288 - published online 9 April 2014 Show/Hide Abstract
Abstract: Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.
Cells2014, 3(2), 258-287; doi:10.3390/cells3020258 - published online 8 April 2014 Show/Hide Abstract
Abstract: Transient receptor potential (TRP) channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human. TRP channels exert a multitude of physiological functions ranging from Ca2+ homeostasis in the kidney to pain reception and vision. These channels are activated by a wide range of stimuli and undergo covalent post-translational modifications that affect and modulate their subcellular targeting, their biophysical properties, or channel gating. These modifications include N-linked glycosylation, protein phosphorylation, and covalent attachment of chemicals that reversibly bind to specific cysteine residues. The latter modification represents an unusual activation mechanism of ligand-gated ion channels that is in contrast to the lock-and-key paradigm of receptor activation by its agonists. In this review, we summarize the post-translational modifications identified on TRP channels and, when available, explain their physiological role.
Cells2014, 3(2), 247-257; doi:10.3390/cells3020247 - published online 4 April 2014 Show/Hide Abstract
Abstract: Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as vasospasm and glomerulosclerosis. When stimulated by agonists of the histamine H1 receptor (H1R), TRPC6 activity decays to the baseline despite the continuous presence of the agonist. In this study, we examined whether H1R desensitization contributes to regulating the decay rate of TRPC6 activity upon receptor stimulation. We employed the HEK expression system and a biosensor allowing us to simultaneously detect the changes in intracellular diacylglycerol (DAG) and Ca2+ concentrations. We found that the histamine-induced DAG response was biphasic, in which a transient peak was followed by maintained elevated plateau, suggesting that desensitization of H1R takes place in the presence of histamine. The application of PKC inhibitor Gö6983 slowed the decay rate of intracellular DAG concentration. Activation of the mouse H1R mutant lacking a putative PKC phosphorylation site, Ser399, responsible for the receptor desensitization, resulted in a prolonged intracellular DAG increase and greater Mn2+ influx through the TRPC6 channel. Thus, our data support the hypothesis that PKC-dependent H1R phosphorylation leads to a reduced production of intracellular DAG that contributes to TRPC6 activity regulation.
Cells2014, 3(2), 236-246; doi:10.3390/cells3020236 - published online 4 April 2014 Show/Hide Abstract
Abstract: The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an effect in enhancing local inflammation in diseases where CDT-producing bacteria are involved, such as Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter jejuni and Helicobacter hepaticus. One special example is the induction of pathological bone destruction in periodontitis. The opportunistic oral pathogen Aggregatibatcer actinoycemetemcomitans, which is involved in the aggressive form of the disease, can regulate the molecular mechanisms of bone remodeling in a manner that favors bone resorption, with the potential involvement of its CDT. The present review provides an overview of all known to-date inflammatory or bone remodeling responses of CDTs produced by various bacterial species, and discusses their potential contribution to the pathogenesis of the associated diseases.
Cells2014, 3(2), 199-235; doi:10.3390/cells3020199 - published online 4 April 2014 Show/Hide Abstract
Abstract: Glioblastoma multiforme is the most frequent, aggressive and fatal type of brain tumor. Glioblastomas are characterized by their infiltrating nature, high proliferation rate and resistance to chemotherapy and radiation. Recently, oncologic therapy experienced a rapid evolution towards “targeted therapy,” which is the employment of drugs directed against particular targets that play essential roles in proliferation, survival and invasiveness of cancer cells. A number of molecules involved in signal transduction pathways are used as molecular targets for the treatment of various tumors. In fact, inhibitors of these molecules have already entered the clinic or are undergoing clinical trials. Cellular receptors are clear examples of such targets and in the case of glioblastoma multiforme, some of these receptors and their ligands have become relevant. In this review, the importance of glioblastoma multiforme in signaling pathways initiated by extracellular tyrosine kinase receptors such as EGFR, PDGFR and IGF-1R will be discussed. We will describe their ligands, family members, structure, activation mechanism, downstream molecules, as well as the interaction among these pathways. Lastly, we will provide an up-to-date review of the current targeted therapies in cancer, in particular glioblastoma that employ inhibitors of these pathways and their benefits.