SnoN/SkiL,a TGFβ signaling mediator

Effective treatment of cancer cells with chemotherapeutic drugs relies on their ability to induce cell death, making the discovery of their mechanisms of action crucial. Arsenic trioxide (As₂O₃), used in the treatment of promyelocytic leukemia (PML), triggers cell death in several solid tumor cell lines including ovarian carcinomas. While As₂O₃ is remarkably cytotoxic in human ovarian cancer cells, its mechanism of action is poorly understood. We recently investigated the effects of As₂O₃ on several transforming growth factor-β (TGFβ) signaling mediators to better understand its cell death mechanism. Indeed, dysregulated (TGFβ) signaling is typical of ovarian cancers. Based on our findings, we propose that As₂O₃ induces a Beclin 1-independent autophagic pathway in ovarian carcinoma cells by modulating SnoN/SkiL expression, implicating SnoN as a novel therapeutic target for ovarian cancers.     

γ-Secretase-regulated signaling pathways, such as notch signaling, mediate the differentiation of hematopoietic stem cells, development of the immune system, and peripheral immune responses

Notch signaling mediates the fates of numerous cells in both invertebrates and vertebrates. In the immune system, Notch signalling contributes to the generation of hematopoietic stem cells (HSCs), the promotion of HSC self-renewal, T lineage commitment, intrathymic T cell development, and peripheral lymphocyte differentiation/activation. The intracellular domain (ICD) of Notch is released from the cell membrane by γ-secretase and translocates to the nucleus to modulate gene expression. Hence, γ-secretase plays a central role in the regulation of Notch signaling. More than five dozen type 1 transmembrane proteins, including amyloid precursor protein, Notch, and Delta, are substrates for γ-secretase and their ICDs are released from the cell membrane. Therefore, it is highly possible that mechanisms similar to Notch signaling may widely contribute to γ-secretase-regulated signaling. Besides Notch, some transmembrane proteins such as CD44 and CSF-1R, which are important for immune responses, have been reported as substrates for γ-secretase. Since the ICDs of these proteins are also released by γ-secretase from the cell membrane and localize to the nucleus, it is thought that these ICDs modulate gene expression. Thus, γ-secretase-regulated signaling, including Notch signaling, may play a wide range of roles in the immune system.     

A novel β2-AR agonist,Higenamine, induces β-arrestin-biased signaling

Science China Life Sciences - The biased ligands in G protein-coupled receptors (GPCRs) have opened new avenues for developing safer and more effective drugs. However, the identification of such...     

Alternative signaling pathways: when, where and why?

Alternative cell signal transduction pathways have been demonstrated in some experimental systems. The importance of their existence has not been completely appreciated. In this review we present the cases of alternative pathways resulted from a survey of the available experimental data. The alternative pathways could show different relationships, i.e., synergistic, redundant, additive, opposite and competitive effects. They could have distinct time courses and cell, organ, sex or species specification. Further, they could happen during physiological or pathological situations, and display differentiated sensitivity. These case studies together imply that alternative signal pathways could be involved in the regulation of cell functions at the pathway level. In-depth understanding of the importance of the alternative pathways will rely on building and exploration of mathematical models.     

Calcium, a signaling molecule in the endoplasmic reticulum?

For many years now, it has been known that Ca2+ is an important signaling molecule in the cytosol of the cell, but emerging evidence suggests that Ca2+ might also play a signaling role in the endoplasmic reticulum. For example, agonist-induced fluctuations in free Ca2+ concentration in the endoplasmic reticulum can affect many functions of the endoplasmic reticulum, including protein synthesis and modification, and interchaperone interactions.     

Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix

The growth factor TGF-β is secreted in a latent complex consisting of three proteins: TGF-β, an inhibitor (latency-associated protein, LAP, which is derived from the TGF-β propeptide) and an ECM-binding protein (one of the latent TGF-β binding proteins, or LTBPs). LTBPs interact with fibrillins and other ECM components and thus function to localize latent TGF-β in the ECM. LAP contains an integrin-binding site (RGD), and several RGD-binding integrins are able to activate latent TGF-β through binding this site. Mutant mice defective in integrin-mediated activators, and humans and mice with fibrillin gene mutations, show the critical role of ECM and integrins in regulating TGF-β signaling.     

Aging,osteoarthritis and transforming growth factor-β signaling in cartilage

Osteoarthritis is a common malady of the musculoskeletal system affecting the articular cartilage. The increased frequency of osteoarthritis with aging indicates the complex etiology of this disease, which includes pathophysiology and joint stability including biomechanics. The balance between anabolic morphogens and growth factors and catabolic cytokines is at the crux of the problem of osteoarthritis. One such signal is transforming growth factor-β (TGF-β). The impaired TGF-β signaling has been identified as a culprit in old mice in a recent article in this journal. This commentary places this discovery in the context of anabolic and catabolic signals and articular cartilage homeostasis in the joint.     

Obg/CtgA, a signaling protein that controls replication, translation, and morphological development?

The recent finding that the ObgE GTPase acts as a replication checkpoint protein in Escherichia coli has important implications. It reveals the existence of a new pathway of replication control by the nucleotide pool and suggests unsuspected links between replication, proteins synthesis, and cellular differentiation.     

Costly signaling,ritual and cooperation: evidence from Candomblé, an Afro-Brazilian religion

The apparent wastefulness of religious ritual represents a puzzle for rational choice theorists and evolutionary scholars. In recent years, it has been proposed that such rituals represent costly signals that promote intragroup cooperation precisely because of the effort and resources they require. This hypothesis was tested over the course of a 14-month long ethnographic study in the northeast of Brazil. The research focused on adherents of Candomblé, an African diasporic religion organized in autonomous congregations primarily located in low-income urban areas. Individuals who reported higher levels of religious commitment behaved more generously in a public goods economic game and revealed more instances of provided and received cooperation within their religious community. This suggests that ritual as a costly signaling may effectively predict willingness to cooperate with other group members and that the signaler may accrue benefits in the form of received cooperation. Socioeconomic variables are also shown to mediate religious signaling. This raises the possibility that signalers strategically alter their expressions of commitment as their needs and circumstances change.     

Spying on IgE receptor signaling: simply complex,or not?

Plasma membrane organization and the potential role, or not, of lipid raft microdomains in signal transduction is a controversial topic. Cross-correlation fluorescent correlation spectroscopy (CC-FCS) shows promise as a new approach to rapidly probe protein-protein interactions in living cells during signal transduction. CC-FCS data from studies of IgE receptor signaling challenge models of large stable lipid raft signaling domains and reveal a new complexity in the dynamic (re)organization of signaling complexes.     

Chemotactic signaling,microglia, and Alzheimer's disease senile plaques: is there a connection?

Chemotactic cells known as microglia are involved in the inflammation associated with pathology in Alzheimer’s disease (AD). We investigate conditions that lead to aggregation of microglia and formation of local accumulations of chemicals observed in AD senile plaques. We develop a model for chemotaxis in response to a combination of chemoattractant and chemorepellent signaling chemicals. Linear stability analysis and numerical simulations of the model predict that periodic patterns in cell and chemical distributions can evolve under local attraction, long-ranged repulsion, and other constraints on concentrations and diffusion coefficients of the chemotactic signals. Using biological parameters from the literature, we compare and discuss the applicability of this model to actual processes in AD. Reprint address. Maternity leave.     

A Gβγ effector, ElmoE, transduces GPCR signaling to the actin network during chemotaxis

Activation of G protein-coupled receptors (GPCRs) leads to the dissociation of heterotrimeric G-proteins into Gα and Gβγ subunits, which go on to regulate various effectors involved in a panoply of cellular responses. During chemotaxis, Gβγ subunits regulate actin assembly and migration, but the protein(s) linking Gβγ to the actin cytoskeleton remains unknown. Here, we identified a Gβγ effector, ElmoE in Dictyostelium, and demonstrated that it is required for GPCR-mediated chemotaxis. Remarkably, ElmoE associates with Gβγ and Dock-like proteins to activate the small GTPase Rac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin. Thus, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. The pathway, consisting of GPCR, Gβγ, Elmo/Dock, Rac, and Arp2/3, spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis.     

All signaling is local?

The mechanism of signal transmission following ligand stimulation of receptor tyrosine kinases in living cells is poorly understood. Recent studies have visualized the spatio-temporal pattern of EGF signaling, indicating that receptor density is an important factor in the mechanism of lateral propagation of local EGF signaling.