Calcium: just a chemical switch?

The calcium-signature hypothesis has evolved as a concept to explain specificity in signaling pathways that utilise calcium as a second messenger. In plant biology, this hypothesis was purely conceptual and based only upon correlative observations until recently. In the past few years, however, empirical data have emerged from experiments that were specifically designed to tackle the question of how specificity is encoded by calcium. In light of the attractive calcium-signature hypothesis, other potential explanations for signalling specificity have been overshadowed and ignored: it has been assumed that the calcium-signature dogma will explain all plant calcium signaling. However, there is a good deal of evidence supporting a counter-hypothesis in which calcium does not itself encode specificity but is merely an essential 'switch' in signaling. At the very least, both hypotheses are likely to be true in different situations, and it may well be that the calcium-signature hypothesis describes the exception rather than the rule.     

As easy as flipping a switch?

Proteins that behave as switches help to establish the complex molecular logic that is central to biological systems. Aspiring to be nature's equal, researchers have successfully created protein switches of their own design; in particular, numerous and varied zinc-triggered switches have been made. Recent studies in which such switches have been readily identified from combinatorial protein libraries support the notion that proteins are primed to show allosteric behavior and that newly created ligand-binding sites will often be functionally coupled to the original activity of the protein. If true, this notion suggests that switch engineering might be more tractable than previously thought, boding well for the basic science, sensing and biomedical applications for which protein switches hold much promise.     

Oxygen: a master regulator of pancreatic development?

Beyond its role as an electron acceptor in aerobic respiration, oxygen is also a key effector of many developmental events. The oxygen‐sensing machinery and the very fabric of cell identity and function have been shown to be deeply intertwined. Here we take a first look at how oxygen might lie at the crossroads of at least two of the major molecular pathways that shape pancreatic development. Based on recent evidence and a thorough review of the literature, we present a theoretical model whereby evolving oxygen tensions might choreograph to a large extent the sequence of molecular events resulting in the development of the organ. In particular, we propose that lower oxygenation prior to the expansion of the vasculature may favour HIF (hypoxia inducible factor)‐mediated activation of Notch and repression of Wnt/β‐catenin signalling, limiting endocrine cell differentiation. With the development of vasculature and improved oxygen delivery to the developing organ, HIF‐mediated support for Notch signalling may decline while the β‐catenin‐directed Wnt signalling is favoured, which would support endocrine cell differentiation and perhaps exocrine cell proliferation/differentiation.     

APC/C – the master controller of origin licensing?

The cyclin kinase inhibitor p27^kip1 acts as a potent tumor supressor protein in a variety of human cancers. Its expression levels correlate closely with the overall prognosis of the affected patient and often predict the outcome to different treatment modalities. In contrast to other tumor suppressor proteins p27 expression levels in tumor cells are frequently regulated by ubiquitin dependent proteolysis. Re-expression of p27 in cancer cells therefore does not require gene therapy but can be achieved by interfering with the protein turnover machinery. In this review we will summarize experimental results which highlight the potential use of p27 as a target for oncological therapies.     

The phosphatidylserine receptor: a crucial molecular switch?

The uptake and removal of necrotic or lysed cells involves inflammation and an immune response, due in part to processes that involve members of the collectin family, surface calreticulin and CD91. Clearance of apoptotic cells, by contrast, does not induce either inflammation or immunity. Could the phosphatidylserine receptor be the molecular switch that determines what the outcome will be?     

Cdk2 as a master of S phase entry: fact or fake?

It has long been believed that Cdk2 and its activator cyclin E play essential roles in the progression of the mitotic cell cycle. However, recent studies using knockout mouse models revealed that neither Cdk2 nor cyclin E are essential in vivo. The purpose of this Perspective is to compare both Cdk2 and cyclin E knockout mice models and to discuss potential mechanisms driving the cell cycle in the absence of Cdk2 or cyclin E. Particular emphasis is placed on possible non-catalytic roles of cyclin E, the expression and activity of the second cyclin binding partner of Cdk2, cyclin A, as well as on the expression and degradation of the Cdk2 inhibitor p27Kip1 in the absence of Cdk2.     

Troponin-tropomyosin: an allosteric switch or a steric blocker?

The interaction of myosin subfragment 1 (S1) with actin-tropomyosin-troponin (regulated actin) is highly nucleotide dependent. The binding of S1 or S1-ADP (but not S1-ATP nor N,N'-rho-phenylenedimaleimide-modified S1-ATP) to regulated actin activates ATP hydrolysis even in the absence of Ca(2+). Investigations with S1 and S1-ADP have led to the idea that some actin sites are directly blocked toward the binding of S1 either by tropomyosin or troponin. The blocked state is thought to occur only at ionic strengths greater than 50 mM. The question is whether nonactivating S1 binding is blocked under the same conditions. We show that troponin inhibits binding of the nonactivating state, N,N'-rho-phenylenedimaleimide-S1-ATP, to actin but only when tropomyosin is absent. A lag in the rate of binding of activating S1 to actin (an indicator of the blocked state) occurs only in the presence of tropomyosin. Thus, tropomyosin inhibits binding of rigor S1 but not S1-ATP-like states. No evidence for an ionic strength-dependent change in the mechanism of regulation was observed either from measurements of the rate of activating S1 binding or from the equilibrium binding of nonactivating S1 to actin. At all conditions examined, N,N'-rho-phenylenedimaleimide-S1-ATP bound to regulated actin in the absence of Ca(2+). These results support the view of regulation in which tropomyosin movement is an allosteric switch that is modulated by activating myosin binding but that does not function solely by regulating myosin binding.     

Is KSHV lytic growth induced by a methylation-sensitive switch?

Both latent and lytic growth of Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) contribute to its pathogenesis. Expression of the immediate-early Lyta/ORF50 gene can single-handedly induce the lytic phase of growth in cells latently infected with KSHV. The recent demonstration that this promoter is regulated by methylation paves the way for further research to understand how the virus makes use of the host's cellular environment to control its life cycle.     

Malate. Jack of all trades or master of a few?

The dicarboxylic acid malate has long been thought to play important roles in plant physiology. In addition to being a major photosynthate in C4 and CAM plants and an intermediate of the tricarboxylic acid cycle it has been proposed to play essential roles in pH regulation and important roles in pathogen response, as a component of the root exudates and as a regulatory osmolyte affecting stomatal function. Recent years have seen the cloning and functional analysis of a wide range of enzymes and transporters associated with malate metabolism. Here we attempt to provide a synthesis of research in this field as well as re-evaluating the role of this metabolite in mediating guard cell function.