Intrinsic limits of information transmission in biochemical signalling motifs

All living things have evolved to sense changes in their environment in order to respond in adaptive ways. At the cellular level, these sensing systems generally involve receptor molecules at the cell surface, which detect changes outside the cell and relay those changes to the appropriate response elements downstream. With the advent of experimental technologies that can track signalling at the single-cell level, it has become clear that many signalling systems exhibit significant levels of ‘noise,’ manifesting as differential responses of otherwise identical cells to the same environment. This noise has a large impact on the capacity of cell signalling networks to transmit information from the environment. Application of information theory to experimental data has found that all systems studied to date encode less than 2.5 bits of information, with the majority transmitting significantly less than 1 bit. Given the growing interest in applying information theory to biological data, it is crucial to understand whether the low values observed to date represent some sort of intrinsic limit on information flow given the inherently stochastic nature of biochemical signalling events. In this work, we used a series of computational models to explore how much information a variety of common ‘signalling motifs’ can encode. We found that the majority of these motifs, which serve as the basic building blocks of cell signalling networks, can encode far more information (4–6 bits) than has ever been observed experimentally. In addition to providing a consistent framework for estimating information-theoretic quantities from experimental data, our findings suggest that the low levels of information flow observed so far in living system are not necessarily due to intrinsic limitations. Further experimental work will be needed to understand whether certain cell signalling systems actually can approach the intrinsic limits described here, and to understand the sources and purpose of the variation that reduces information flow in living cells.

Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux

Although studies in recombinant cells indicate that scavenger receptor class B, type I (SR-BI) can promote cholesterol efflux, investigations in transgenic mice overexpressing or deficient in SR-BI endorse its physiological function as selectively sequestering cholesteryl esters from high-density lipoproteins (HDLs). Less clear is the role of SR-BII, a splice variant of the SR-B gene that differs only in the C-terminal cytoplasmic domain. Here, we identify several putative signalling motifs in the C-terminus of human SR-BII, which are absent from SR-BI, and hypothesize that these motifs interact with signalling molecules to mobilize stored cholesteryl esters and/or promote the efflux of intracellular free cholesterol. ‘Pull-down’ assays using a panel of tagged SH3 (Src homology 3) domains showed that cytoplasmic SR-BII, but not cytoplasmic SR-BI, bound the SH3 domain of phospholipase C-γ1; this interaction was not, however, detected under more physiological conditions. Specific anti-peptide antisera identified SR-BII in human monocyte/macrophage THP-1 cells and, in recombinant cells, revealed receptor localization to caveolae, a plasma membrane microdomain that concentrates signal-transducer molecules and acts as a conduit for cholesterol flux between cells and lipoproteins. Consistent with its caveolar localization, expression of human SR-BII in recombinant Chinese hamster ovary cells (CHO–SR-BII) was associated with increased HDL-mediated cholesterol efflux. Nevertheless, when CHO-SR-BII cells were pre-loaded with cholesteryl [3H]oleate and incubated with HDL, cholesteryl ester stores were not reduced compared with control cells. We conclude that although human SR-BII is expressed by macrophages, contains cytoplasmic signalling motifs and localizes to caveolae, its ability to stimulate cholesterol efflux does not reflect enhanced hydrolysis of stored cholesteryl esters.

New I-type lectins of the CD 33-related siglec subgroup identified through genomics

Siglecs are sialic-acid-binding proteins of the Ig superfamily that are involved in cell–cell interactions and signalling. In recent years, several novel siglecs that are highly related to CD33/Siglec-2 have been identified through genomics and functional screens. In addition to their distinct sialic-acid-binding properties, most of these novel siglecs bear tyrosine-based signalling motifs that are typically found in inhibitory receptors of the immune system. The restricted expression patterns of CD33-related siglecs in the haemopoietic and immune systems suggests that they are involved in regulating leucocyte activation during inflammatory and immune responses.

Gene structure of mouse BIT/SHPS-1

BIT/SHPS-1/SIRPα/P84 is a unique molecule with a high degree of homology with immune antigen recognition molecules (immunoglobulin, T-cell receptor and MHC), and is highly expressed in the brain. The extracellular region contains three immunoglobulin-like domains (V-type, C1-type and C1-type), and the intracellular region contains two signalling motifs that interact with SHP-2 protein tyrosine phosphatase. BIT-coated plates support cell-substrate adhesion and neurite extension of neurons, and BIT participates in neuronal signal transduction. Diversity of the V-type domain sequences of human BIT has been reported. In the present study we analysed the structure of the mouse BIT gene (Bit). The protein coding region consists of eight exons corresponding to a signal peptide, a V-type domain, a C1-type domain, a C1-type domain, a transmembrane region and three parts of one cytoplasmic region. The two signalling motifs are encoded in one exon. Four splicing forms of mouse BIT were revealed. We also found the sequence diversity in three mouse strains, namely BALB/c, 129/Sv and C57BL/6. The substitution patterns of amino acids and nucleotides indicate positive pressure to alter the amino acids in the V-type domain in evolution. Immunoblot analyses showed that mouse BIT and human BITα are predominantly expressed in the brain. On the bases of these findings we discuss the possibility that BIT contributes to the genetic individuality and diversity of the brain.