The diacylglycerol lipases: structure,regulation and roles in and beyond endocannabinoid signalling

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB₁ and CB₂ cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB₁ receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson''s disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity—however, key insights can be gleaned by homology modelling against other α/β hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.     

WASH, WHAMM and JMY: regulation of Arp2/3 complex and beyond

Arp2/3 complex mediates the nucleation of actin filaments in multiple subcellular processes, and is activated by nucleation-promoting factors (NPFs) from the Wiskott-Aldrich Syndrome family. In exciting new developments, this family has grown by three members: WASH, WHAMM and JMY, which extend the repertoire of dynamic membrane structures that are remodeled following Arp2/3 activation in vivo. These novel NPFs share an actin- and Arp2/3-interacting WCA module, and combine Arp2/3 activation with additional biochemical functions, including capping protein inhibition, microtubule engagement or Arp2/3-independent actin nucleation, none of which had been previously associated with canonical WCA-harboring proteins. Uncovering the physiological relevance of these unique activities will require concerted efforts from multiple disciplines, and is sure to impact our understanding of how the cytoskeleton controls so many dynamic subcellular events.     

Costly signalling theories: beyond the handicap principle

Two recent overviews of costly signalling theory—Maynard-Smith and Harper (2003) and Searcy and Nowicki (2005)—both refuse to count signals kept honest by punishment of dishonesty, as costly signals, because (1) honest signals must be costly in cases of costly signalling, and (2) punishment of dishonesty itself requires explanation. I argue that both pairs of researchers are mistaken: (2) is not a reason to discount signals kept honest by punishment of dishonesty as cases of costly signalling, and (1) betrays too narrow a focus on certain versions of costly signalling theory. In the course of so arguing, I propose a new schema for classifying signal costs, which suggests productive research questions for future conceptual and empirical work on costly signalling.     

Plastid signalling to the nucleus and beyond

Communication between the compartments or organelles of cells is essential for plant growth and development. There is an emerging understanding of signals generated within energy-transducing organelles, such as chloroplasts and mitochondria, and the nuclear genes that respond to them, a process known as retrograde signalling. A recent series of unconnected breakthroughs have given scientists a glimpse inside the 'black box' of organellar signalling thanks to the identification of some of the factors involved in generating and propagating signals to the nucleus and, in some instances, systemically throughout photosynthetic tissues. This review will focus on recent developments in our understanding of retrograde and systemic signals generated by organelles, with an emphasis on chloroplasts.     

A Hippo in the ointment: MST signalling beyond the fly

The regulation of cell cycle and apoptosis is fundamental to the control of cell growth and organism homeostasis. Failure to efficiently regulate these processes often results in the increased cell growth observed in tumours. Accumulation of genetic lesions frequently eliminates these regulatory steps so it is imperative that multiple signalling pathways are employed to ensure that efficient control is maintained. Over the last few years a novel signalling pathway entered the limelight that prevents inappropriate activation of the cell cycle and can elicit apoptosis to limit cell numbers. Denoted the MST/hippo pathway, it is involved in regulating cell number in organism development and tumour progression. Here we aim to review the evidence for a conserved pathway from flies to mammals, and of equal importance to initiate the discussion on the additional cellular and signalling processes that have been adopted by this pathway to achieve further regulation and diversified cellular outcomes in mammals.     

The anaphase-promoting complex: proteolysis in mitosis and beyond

Key events in mitosis such as sister chromatid separation and subsequent inactivation of cyclin-dependent kinase 1 are regulated by ubiquitin-dependent proteolysis. These events are mediated by the anaphase-promoting complex (APC), a cell cycle-regulated ubiquitin ligase that assembles multiubiquitin chains on regulatory proteins such as securin and cyclins and thereby targets them for destruction by the 26S proteasome.     

Cell signalling and gene regulation

A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Plant Biology.     

Cell signalling and gene regulation

A selection of World Wide Web sites relevant to papers published in this issue of Current Opinion in Plant Biology.     

Glutamate in plants: metabolism, regulation, and signalling

Glutamate occupies a central position in amino acid metabolism in plants. The acidic amino acid is formed by the action of glutamate synthase, utilizing glutamine and 2-oxoglutarate. However, glutamate is also the substrate for the synthesis of glutamine from ammonia, catalysed by glutamine synthetase. The alpha-amino group of glutamate may be transferred to other amino acids by the action of a wide range of multispecific aminotransferases. In addition, both the carbon skeleton and alpha-amino group of glutamate form the basis for the synthesis of gamma-aminobutyric acid, arginine, and proline. Finally, glutamate may be deaminated by glutamate dehydrogenase to form ammonia and 2-oxoglutarate. The possibility that the cellular concentrations of glutamate within the plant are homeostatically regulated by the combined action of these pathways is examined. Evidence that the well-known signalling properties of glutamate in animals may also extend to the plant kingdom is reviewed. The existence in plants of glutamate-activated ion channels and their possible relationship to the GLR gene family that is homologous to ionotropic glutamate receptors (iGluRs) in animals are discussed. Glutamate signalling is examined from an evolutionary perspective, and the roles it might play in plants, both in endogenous signalling pathways and in determining the capacity of the root to respond to sources of organic N in the soil, are considered.     

Intracellular signalling controlling integrin activation in lymphocytes

Since the discovery that integrins at the surface of lymphocytes undergo dynamic changes in their adhesive activity after stimulation through the T-cell receptor or stimulation with chemokines, intensive research has been carried out in an attempt to clarify the signalling events that lead to the activation of integrins. Whereas structural studies have provided us with a vivid picture of the conformational flexibility of integrins, the signalling pathways that regulate these conformational changes (known as inside-out signalling) have been elusive. However, as I discuss here, recent studies have provided new insight into the pathways that control the regulation of integrin activity and the coordination of complex cellular functions, such as the homing of lymphocytes and the formation of an immunological synapse.