Membrane guanylate cyclase signal transduction system

The suspect role of the receptor-mediated cyclic GMP signaling pathway was dispelled by the discovery of a membrane guanylate cyclase that was also an atrial natriuretic factor receptor. It is now established that the membrane guanylate cyclase transduction system is linked to the signaling of natriuretic factors, guanylin/enterotoxin, and emerging evidence suggests that a new neural tissue-specific subfamily of membrane guanylate cyclases exists whose mechanism of signal transduction is different from those of the other membrane cyclases. This review will briefly discuss the fascinating, albeit turbulent, history of this signal transduction field, which will be followed by its current status and finally the direction it is heading.     

Oncogenes and signal transduction

Cancer biologists now have a unified concept to guide their search for specific genetic abnormalities and new therapeutic approaches: The genes and proteins that participate in the conversion of normal into malignant cells are also involved in the key process that converts extracellular signals into intracellular events that culminate in division and growth.     

Roles of the JAK-STAT system in signal transduction via cytokine receptors

JAK-STAT signaling pathways are known to play an essential role in the specific activation of interferon-inducible genes. Many cytokines interacting with the cytokine receptor superfamily also appear to activate these pathways. Recent evidence indicates that JAKs play an essential role(s) in cytokine receptor signaling, including both specific pathways linked to STATs and general pathways regulating cell growth and functions.     

A role for CD5 in TCR-mediated signal transduction and thymocyte selection

CD5 is a transmembrane protein that is expressed on the surface of T cells and a subset of B cells. The absence of CD5 rendered thymocytes hyperresponsive to stimulation through the T cell antigen receptor (TCR) in vitro. Selection of T cells expressing three distinct transgenic TCRs was also abnormal in CD5-deficient mice. These observations indicate that CD5 can influence the fate of developing thymocytes by acting as a negative regulator of TCR-mediated signal transduction.     

Phosphatidate phosphohydrolase and signal transduction

A Mg(2+)-independent and N-ethylmaleimide-insensitive phosphatidate phosphohydrolase (PAP-2) has been identified in the plasma membrane of cells and it has been purified. The enzyme is a multi-functional phosphohydrolase that can dephosphorylate phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1-phosphate and these substrates are competitive inhibitors of the reaction. The action of PAP-2 could terminate signalling by these bioactive lipids and at the same time generates compounds such as diacylglycerol, sphingosine and ceramide which are also potent signalling molecules. In relation to phosphatidate metabolism, sphingosine (or sphingosine 1-phosphate) stimulates phospholipase D and thus the formation of phosphatidate. At the same time sphingosine inhibits PAP-2 activity thus further increasing phosphatidate concentrations. By contrast, ceramides inhibit the activation of phospholipase D by a wide variety of agonists and increase the dephosphorylation of phosphatidate, lysophosphatidate, sphingosine 1-phosphate and ceramide 1-phosphate. These actions demonstrate "cross-talk' between the glycerolipid and sphingolipid signalling pathways and the involvement of PAP-2 in modifying the balance of the bioactive lipids generated by these pathways during cell activation.