Lymphokine signal transduction

Lymphokines are a group of signalling molecules involved in communication between cells, mainly those of the immune system. The lymphokines are multi-functional and most of them have mitogenic or co-mitogenic activity. An understanding of lymphokine biology is essential to understand how the immune system develops and functions and to provide a rationale for their use in immunotherapy.The potential to understand the cell biology of the lymphokines has recently become more apparent as molecular biological techniques have first of all produced recombinant factors and secondly have provided clues to the signal transduction pathways by cloning receptors, applying site-directed mutational analysis and also probing for specific promoters and enhancers that are activated along the signal pathway.This review discusses the information that has come from these recent analyses which blends with the biochemical analysis of the second messenger systems in an effort to understand the signalling pathways of the lymphokines.     

VEGF-receptor signal transduction

The vascular endothelial growth factor (VEGF) family of ligands and receptors has been the focus of attention in vascular biology for more than a decade. There is now a consensus that the VEGFs are crucial for vascular development and neovascularization in physiological and pathological processes in both embryo and adult. This has facilitated a rapid transition to their use in clinical applications, for example, administration of VEGF ligands to enhance vascularization of ischaemic tissues and, conversely, inhibitors of VEGF-receptor function in anti-angiogenic therapy. More recent data indicate essential roles for the VEGFs in haematopoietic cell function and in lymphangiogenesis.     

Redox-dependent signal transduction

Reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide appear to be transiently produced in response to growth factor and cytokine stimulation. A variety of evidence suggests that this ligand-stimulated change in the cellular redox state participates in downstream signal transduction. This review will focus on the effects of ROS on signal transduction pathways, the molecules that regulate intracellular ROS production and the potential protein targets of oxidants.     

Gibberellin signal transduction

Recent studies using biochemical and genetic approaches have identified a number of components, including several negative regulators, of the gibberellin (GA) signal transduction pathway in higher plants. The basal state of GA signaling is likely to be repressive, and the GA signal seems to activate the pathway by de-repression to allow GA-stimulated growth and development.     

Calcium signal compartmentalization

Cytosolic calcium signals are produced by suddenly increasing the concentration of free calcium ions (Ca2+). This can occur by opening channels permeable to Ca2+ either in the surface cell membrane or in the membranes of intracellular organelles containing high Ca2+ concentrations. Ca2+ signals can control several different processes, even in the same cell. In pancreatic acinar cells, for example, Ca2+ signals do not only control the normal secretion of digestive enzymes, but can also activate autodigestion and programmed cell death. Recent technical advances have shown that different patterns of Ca2+ signals can be created, in space and time, which allow specific cellular responses to be elicited. The mechanisms responsible for Ca2+ signal compartmentalization are now largely known and will be described on the basis of recent studies of Ca2+ transport pathways and their regulation in pancreatic acinar cells. It turns out that the Ca2+ handling as well as the structural characteristics of the endoplasmic reticulum (ER) and the mitochondria are of particular importance. Using a variety of Ca(2+)-sensitive fluorescent probes placed in different sub-cellular compartments in combination with local uncaging of caged Ca2+, many new insights into Ca2+ signal generation, compartmentalization and termination have recently been obtained.     

Serotonin's SOS signal

Neurotransmitters relay signals within the brain and to peripheral tissues, allowing communication between nerve cells. New work from in this issue of Cell Metabolism reveals that, in C. elegans, serotonin functions during conditions of stress through the well-characterized insulin/IGF-1 signaling pathway, suggesting a mechanism for the stress response.     

ABA signal transduction

Recent advances in the study of abscisic acid signal transduction include the identification of cyclic ADP-ribose as a central mediator of abscisic acid responses. The characterisation of type 2C protein phosphatases, ABI1 and ABI2, implicates negative control and redundant action on the signal pathway of this hormone. In addition, abscisic acid-mediated inhibition of gibberellin-stimulated responses seems to depend on the activation of a phospholipase D during induction of alpha-amylase in barley aleurone cells as well as on a putative acetyltransferase involved in elongation growth.     

Enzyme localization can drastically affect signal amplification in signal transduction pathways

Push–pull networks are ubiquitous in signal transduction pathways in both prokaryotic and eukaryotic cells. They allow cells to strongly amplify signals via the mechanism of zero-order ultrasensitivity. In a push–pull network, two antagonistic enzymes control the activity of a protein by covalent modification. These enzymes are often uniformly distributed in the cytoplasm. They can, however, also be colocalized in space; for instance, near the pole of the cell. Moreover, it is increasingly recognized that these enzymes can also be spatially separated, leading to gradients of the active form of the messenger protein. Here, we investigate the consequences of the spatial distributions of the enzymes for the amplification properties of push–pull networks. Our calculations reveal that enzyme localization by itself can have a dramatic effect on the gain. The gain is maximized when the two enzymes are either uniformly distributed or colocalized in one region in the cell. Depending on the diffusion constants, however, the sharpness of the response can be strongly reduced when the enzymes are spatially separated. We discuss how our predictions could be tested experimentally.     

A novel endocytosis signal related to the KKXX ER-retrieval signal.

Membrane proteins often contain a sorting signal in their cytoplasmic tail that promotes their clustering into coated vesicles at a specific cellular site. ERGIC-53 contains a cytoplasmic ER-retrieval signal, KKFF. However, overexpressed ERGIC-53 is transported to the cell surface and rapidly endocytosed. Here we report that ERGIC-53 carries a previously undescribed endocytosis signal. Surprisingly, the signal was KKFF and like the ER-retrieval signal required a C-terminal position. In fact, the minimal consensus sequence determined by substitutional mutagenesis (K-K/R-F/Y-F/Y) was related to the ER-retrieval consensus (K-K-X-X). Furthermore, we provide evidence that internalization of VIP36, a protein that cycles between plasma membrane and Golgi, is mediated by a signal at its C-terminus that matches the internalization consensus sequence. The relatedness of the two signals suggests that coatomer-mediated retrieval of proteins may be mechanistically more related to clathrin-dependent sorting than previously anticipated.     

PII signal transduction proteins

PII proteins, found in Bacteria, Archaea and plants, help coordinate carbon and nitrogen assimilation by regulating the activity of signal transduction enzymes in response to diverse signals. Recent studies of bacterial PII proteins have revealed a solution to the signal transduction problem of how to coordinate multiple receptors in response to diverse stimuli yet permit selective control of these receptors under various conditions and allow adaptation of the system as a whole to long-term stimulation.     

Oxygen signal transduction

Although manifestations of O2 adaptation have long been examined, only now are biochemical mechanisms of O2 regulation beginning to be understood. This article comments on the current state of knowledge about proteins that function as direct sensors of molecular oxygen and makes predictions about as yet undiscovered sensors.     

Kinesin carries the signal

Conventional kinesin has long been known to be a molecular motor that transports vesicular cargo, but only recently have we begun to understand how it functions in cells. Regulation of kinesin involves self-inhibition in which a head-to-tail interaction prevents microtubule binding. Although the mechanism of motor activation remains to be clarified, recent progress with respect to cargo binding might provide a clue. Kinesin binds directly to the JIPs (JNK-interacting proteins), identified previously as scaffolding proteins in the JNK (c-Jun NH(2)-terminal kinase) signaling pathway. The JIPs can allow kinesin to transport many different cargoes and to concentrate and respond to signaling pathways at certain sites within the cell. The use of scaffolding proteins could be a general mechanism by which molecular motors link to their cargoes.     

核钙信号

尽管核周隙与内质网的腔相通,核膜上存在钙信号分子的受体等事实表明,细胞核存在一套相对独立的钙信号机制。作为核钙的贮存库,核被是核钙信号的发源地。核被中钙离子的充盈状态影响着核孔复合体的构象,从而调节核质间物质交流。已有证据显示,核钙信号与胞质钙信号在基因转录中的作用有所区别。核钙信号在细胞凋亡中发挥重要作用,其中,钙蛋白酶起着较为关键的作用。核钙信号研究为完整理解钙信号的生理功能开辟了新视野。     

The nuclear location signal

A short sequence of predominantly basic amino acids Pro-Pro-Lys-Lys-Lys-Arg-Lys-Val from SV40 Large T is responsible for the normal nuclear location of the protein. Alteration of Lys-128 to each of six different residues other than Arg renders Large T cytoplasmic, whereas single amino acid changes in the surrounding region impair but do not prevent nuclear accumulation. When transposed to the amino terminus of cytoplasmic Large T species, or Escherichia coli beta-galactosidase or of chicken muscle pyruvate kinase, the sequence around Lys-128 of Large T is able to direct the recipient protein to the nucleus. This demonstrates that these amino acids can be sufficient for nuclear location and can act as a nuclear location signal. A computer search of over 2500 proteins reveals that some other nuclear proteins (for example, BK virus Large T, SV40 VP2 and adenovirus 72kDa DNA binding protein) contain very similar basic tracts, but so too do some presumed non-nuclear proteins (for example, poliovirus VP3). We suggest that the related sequence acts as the nuclear location signal in the other nuclear proteins but that the sequence does not function in all cases, perhaps because it is not accessible. A similar, but shorter or less basic sequence, was detected in a number of other nuclear proteins, for example, polyoma virus Large T, SV40 VP1 and several histones. However, such sequences were also found in many other proteins. Perhaps the shorter basic sequences can also act as nuclear location signals, but to be functional they need to be exposed (for example, at the amino terminus of the protein as in SV40 VP1) or to be present in multiple copies.