Extracellular Signalling Modulates Scar/WAVE Complex Activity through Abi Phosphorylation

The lamellipodia and pseudopodia of migrating cells are produced and maintained by the Scar/WAVE complex. Thus, actin-based cell migration is largely controlled through regulation of Scar/WAVE. Here, we report that the Abi subunit—but not Scar—is phosphorylated in response to extracellular signalling in Dictyostelium cells. Like Scar, Abi is phosphorylated after the complex has been activated, implying that Abi phosphorylation modulates pseudopodia, rather than causing new ones to be made. Consistent with this, Scar complex mutants that cannot bind Rac are also not phosphorylated. Several environmental cues also affect Abi phosphorylation—cell-substrate adhesion promotes it and increased extracellular osmolarity diminishes it. Both unphosphorylatable and phosphomimetic Abi efficiently rescue the chemotaxis of Abi KO cells and pseudopodia formation, confirming that Abi phosphorylation is not required for activation or inactivation of the Scar/WAVE complex. However, pseudopodia and Scar patches in the cells with unphosphorylatable Abi protrude for longer, altering pseudopod dynamics and cell speed. Dictyostelium, in which Scar and Abi are both unphosphorylatable, can still form pseudopods, but migrate substantially faster. We conclude that extracellular signals and environmental responses modulate cell migration by tuning the behaviour of the Scar/WAVE complex after it has been activated.

Extracellular signalling modulates Scar/WAVE complex activity through Abi phosphorylation

The lamellipodia and pseudopodia of migrating cells are produced and maintained by the Scar/WAVE complex. Thus, actin-based cell migration is largely controlled through regulation of Scar/WAVE. Here we report that the Abi subunit - not Scar/WAVE - is phosphorylated in response to extracellular signalling. Like Scar, Abi is phosphorylated after the complex has been activated, implying that Abi phosphorylation modulates pseudopodia, rather than causing new ones to be made. Consistent with this, Scar/WAVE complex mutants that cannot bind Rac are also not phosphorylated. Several environmental cues also affect Abi phosphorylation - cell-substrate adhesion promotes it and increased extracellular osmolarity diminishes it. Both unphosphorylatable and phosphomimetic Abi efficiently rescue the chemotaxis of Abi KO cells and pseudopodia formation, confirming that Abi phosphorylation is not required for activation or inactivation of the Scar/WAVE complex. However, pseudopodia and Scar/WAVE patches in the cells with unphosphorylatable Abi protrude for longer, altering pseudopod dynamics and cell speed. Cells in which Scar and Abi are both unphosphorylatable can still form pseudopods, but migrate substantially faster. We conclude that extracellular signals and environmental responses modulate cell migration by tuning the behaviour of the Scar/WAVE complex after it has been activated.

Geoffrey Burnstock. 10 May 1929—3 June 2020

Geoffrey Burnstock was a biomedical scientist who gained renown for his discovery that adenosine 5′-triphosphate (ATP) functions as an extracellular signalling molecule. Born in London and educated at King's and University colleges, he did postdoctoral work at Mill Hill and Oxford. He moved in 1959 to the Department of Zoology at the University of Melbourne because he sensed there a greater freedom to challenge established thinking in physiology. His group found that transmission from sympathetic and parasympathetic autonomic nerves to smooth muscle was in some places not mediated by the accepted chemical messengers (noradrenaline and acetylcholine). He amassed evidence that ATP was this non-adrenergic, non-cholinergic transmitter, using biochemical, histological and electrophysiological approaches: heretically, he styled this ‘purinergic transmission’. Geoff further upset dogma in the 1970s by proposing ‘co-transmission’ in which some nerves released ATP in addition to either noradrenaline or acetylcholine. He distinguished pharmacologically P1 receptors (activated best by adenosine and blocked by xanthines) and P2 receptors (activated best by purine nucleotides such as ATP) and he proposed in 1985 that the latter embraced P2X (ion channel) and P2Y (G protein-coupled) subtypes: about 10 years later these categories were substantiated by cDNA cloning. From 1975 until his retirement in 1997, Geoff was head of the Department of Anatomy and Embryology at University College London (UCL), which he developed energetically into a large and strong research department. Later, as head of the Autonomic Research Institute at the Royal Free (part of UCL), he continued to collaborate extensively, and founded several journals and international professional societies. He widely sought clinical benefit for his discoveries, and both P2X and P2Y receptors have been developed as the targets of useful therapeutics (gefapixant, clopidogrel). Geoff was proud of his modest, rather humble, background and eschewed formality. He may have smiled when his early discoveries were met with cynicism, even ridicule (‘pure-imagine’ transmission noted one amusing critic), but this just reinforced his resolve and encouraged his encyclopaedic oeuvre.

Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS

Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment—in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP–CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions.

The crosstalk between microtubules, actin and membranes shapes cell division

Mitotic progression is orchestrated by morphological and mechanical changes promoted by the coordinated activities of the microtubule (MT) cytoskeleton, the actin cytoskeleton and the plasma membrane (PM). MTs assemble the mitotic spindle, which assists sister chromatid separation, and contact the rigid and tensile actomyosin cortex rounded-up underneath the PM. Here, we highlight the dynamic crosstalk between MTs, actin and cell membranes during mitosis, and discuss the molecular connections between them. We also summarize recent views on how MT traction forces, the actomyosin cortex and membrane trafficking contribute to spindle positioning in isolated cells in culture and in epithelial sheets. Finally, we describe the emerging role of membrane trafficking in synchronizing actomyosin tension and cell shape changes with cell–substrate adhesion, cell–cell contacts and extracellular signalling events regulating proliferation.

Decoding the mystery of how bacteria “talk”: Among Gram-negative microorganisms

To date, microbial diversity is still the least well understood component of biodiversity. Bacteria are the most abundant microorganisms where most species are often found ubiquitous. Microorganisms such as bacteria are diverse in their impacts such as in spreading of infectious diseases or play a valuable role in biotechnological purposes. Hence, it is interesting to gain a look upon the ways where bacteria regulate their daily processes in the environment. Bacteria communicate with each other through extracellular signalling molecules or also known as autoinducers (AIs) that are produced, detected and show response. This process is termed as quorum sensing (QS) which indicates that bacteria do communicate in order to perform various physiological activities. QS enable bacteria to have the advantages that are unattainable as individual bacterial cell. This review emphases on the characteristics of quorum sensing (QS) and its benefits in understanding different kind of bacterial QS-dependent activities. This fundamental insight from QS system will enable us to manage bacterial activities by targeting their communication circuit.

The transcription factor E2A drives neural differentiation in pluripotent cells

The intrinsic mechanisms that link extracellular signalling to the onset of neural differentiation are not well understood. In pluripotent mouse cells, BMP blocks entry into the neural lineage via transcriptional upregulation of Inhibitor of Differentiation (Id) factors. We have previously identified that the major binding partner of Id proteins in pluripotent cells is the basic helix-loop-helix (bHLH) transcription factor (TF), E2A. Id1 can prevent E2A from forming heterodimers with bHLH TFs or from forming homodimers. Here, we show that overexpression of a forced E2A homodimer is sufficient to drive robust neural commitment in pluripotent cells, even under non-permissive conditions. Conversely, we find that E2A null cells display a defect in their neural differentiation capacity. E2A acts as an upstream activator of neural lineage genes, including Sox1 and Foxd4, and as a repressor of Nodal signalling. Our results suggest a crucial role for E2A in establishing neural lineage commitment in pluripotent cells.

Ancient origins of arthropod moulting pathway components

Ecdysis (moulting) is the defining character of Ecdysoza (arthropods, nematodes and related phyla). Despite superficial similarities, the signalling cascade underlying moulting differs between Panarthropoda and the remaining ecdysozoans. Here, we reconstruct the evolution of major components of the ecdysis pathway. Its key elements evolved much earlier than previously thought and are present in non-moulting lophotrochozoans and deuterostomes. Eclosion hormone (EH) and bursicon originated prior to the cnidarian-bilaterian split, whereas ecdysis-triggering hormone (ETH) and crustacean cardioactive peptide (CCAP) evolved in the bilaterian last common ancestor (LCA). Identification of EH, CCAP and bursicon in Onychophora and EH, ETH and CCAP in Tardigrada suggests that the pathway was present in the panarthropod LCA. Trunk, an ancient extracellular signalling molecule and a well-established paralog of the insect peptide prothoracicotropic hormone (PTTH), is present in the non-bilaterian ctenophore Mnemiopsis leidyi. This constitutes the first case of a ctenophore signalling peptide with homology to a neuropeptide.

Purine and purinergic receptors

Adenosine 5′-triphosphate acts as an extracellular signalling molecule (purinergic signalling), as well as an intracellular energy source. Adenosine 5′-triphosphate receptors have been cloned and characterised. P1 receptors are selective for adenosine, a breakdown product of adenosine 5′-triphosphate after degradation by ectonucleotidases. Four subtypes are recognised, A1, A2A, A2B and A3 receptors. P2 receptors are activated by purine and by pyrimidine nucleotides. P2X receptors are ligand-gated ion channel receptors (seven subunits (P2X1-7)), which form trimers as both homomultimers and heteromultimers. P2Y receptors are G protein-coupled receptors (eight subtypes (P2Y1/2/4/6/11/12/13/14)). There is both purinergic short-term signalling and long-term (trophic) signalling. The cloning of P2X-like receptors in primitive invertebrates suggests that adenosine 5′-triphosphate is an early evolutionary extracellular signalling molecule. Selective purinoceptor agonists and antagonists with therapeutic potential have been developed for a wide range of diseases, including thrombosis and stroke, dry eye, atherosclerosis, kidney failure, osteoporosis, bladder incontinence, colitis, neurodegenerative diseases and cancer.