There has recently been rapid progress in understanding receptors that generate intracellular signals from inositol lipids. One of these lipids, phosphatidylinositol 4,5-bisphosphate, is hydrolysed to diacylglycerol and inositol trisphosphate as part of a signal transduction mechanism for controlling a variety of cellular processes including secretion, metabolism, phototransduction and cell proliferation. Diacylglycerol operates within the plane of the membrane to activate protein kinase C, whereas inositol trisphosphate is released into the cytoplasm to function as a second messenger for mobilizing intracellular calcium.

Inositol trisphosphate, a novel second messenger in cellular signal transduction.

The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

The Calpain System

https://cbs.umn.edu/sites/cbs.umn.edu/files/public/downloads/2004-Sarbassov.pdf

Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.

A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed. Cell Death and Differentiation (2003) 10, 45–65. doi:10.1038/ sj.cdd.4401189

/pdf/tumor-necrosis-factor-signaling-4agufl4zu9.pdf

Tumor necrosis factor signaling.

The polymorphic fungus Candida albicans is a member of the normal human microbiome. In most individuals, C. albicans resides as a lifelong, harmless commensal. Under certain circumstances, however, C. albicans can cause infections that range from superficial infections of the skin to life-threatening systemic infections. Several factors and activities have been identified which contribute to the pathogenic potential of this fungus. Among them are molecules which mediate adhesion to and invasion into host cells, the secretion of hydrolases, the yeast-to-hypha transition, contact sensing and thigmotropism, biofilm formation, phenotypic switching and a range of fitness attributes. Our understanding of when and how these mechanisms and factors contribute to infection has significantly increased during the last years. In addition, novel virulence mechanisms have recently been discovered. In this review we present an update on our current understanding of the pathogenicity mechanisms of this important human pathogen.

/pdf/candida-albicans-pathogenicity-mechanisms-vbzhb0mq5w.pdf

Candida albicans pathogenicity mechanisms

Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation.

Publisher Summary This chapter discusses the role of signal-transducing phospholipases A 2 , C, and D in platelet activation. One of the initial responses of platelets stimulated with thrombin is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP,) by phosphoinositide-specific phospholipase C (PI-PLC). This results in the generation of the second messengers inositol 1,4,5-trisphosphate (IP,) and 1,2-diacylglycerol (DG). This initial and transient DG formation is followed by a larger, sustained DG accumulation, which may trigger translocation of protein kinase C (PKC) and platelet aggregation. Although recent evidence indicates that posphatidylcholine (PC) hydrolysis by PC-specific PLC andor phospholipase D (PLD) is the primary pathway for generation of DG and phosphatidic acid (PA), the second phase of DG accumulation appears to derive primarily from phosphatidylinositol (PI) in the platelet. Platelets contain multiple PI-PLC isoforms, which may coordinately regulate phosphoinositide hydrolysis. Secondary aggregation and secretion in response to collagen, ADP, and epinephrine are largely dependent on the formation ofcyclooxygenaseproducts of arachidonic acid (AA). The liberation of AA mainly by the action of phospholipase A 2 (PLA 2 ) is the rate-limiting step for the generation of AAmetabolites. Taken together, various signal-transducing phospholipases play key roles in platelet receptor activation under the separate and integrated regulation.

The Role of Signal-Transducing Phospholipases A22, C, and D in Platelet Activation

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Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation.

The Role of Signal-Transducing Phospholipases A22, C, and D in Platelet Activation