The integrins

The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. They are transmembrane αβ heterodimers and at least 18 α and eight β subunits are known in humans, generating 24 heterodimers. Members of this family have been found in mammals, chicken and zebrafish, as well as lower eukaryotes, including sponges, the nematode Caenorhabditis elegans (two α and one β subunits, generating two integrins) and the fruitfly Drosophila melanogaster (five α and one β, generating five integrins). The α and β subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer. The sequence arginine-glycine-aspartic acid (RGD) was identified as a general integrin-binding motif, but individual integrins are also specific for particular protein ligands. Immunologically important integrin ligands are the intercellular adhesion molecules (ICAMs), immunoglobulin superfamily members present on inflamed endothelium and antigen-presenting cells. On ligand binding, integrins transduce signals into the cell interior; they can also receive intracellular signals that regulate their ligand-binding affinity. Here we provide a brief overview that concentrates mostly on the organization, structure and function of mammalian integrins, which have been more extensively studied than integrins in other organisms.     

Epithelial integrins

The integrin family was originally described as a family of adhesion receptors, utilized by cells for attachment to and migration across components of the extracellular matrix. Epithelial cells in adult tissues are generally stationary cells, but these cells nevertheless express several different integrins. This review will discuss the evidence that integrins on epithelial cells are also likely to function as signaling molecules, allowing these cells to detect attachment or detachment, and changes in the local composition of ligands. Signals initiated by integrins appear to modulate epithelial cell differentiation, proliferation, survival, and gene expression. Because the local concentration of integrin ligands is altered by injury, inflammation, and remodeling, signals initiated through integrins are likely to play important roles in the responses of epithelial cells to each of these processes.     

Clustered protocadherin family

The brain is a complex system composed of enormous numbers of differentiated neurons, and brain structure and function differs among vertebrates. To examine the molecular mechanisms underlying brain structure and function, it is important to identify the molecules involved in generating neural diversity and organization. The clustered protocadherin (Pcdh) family is the largest subgroup of the diverse cadherin superfamily. The clustered Pcdh proteins are predominantly expressed in the brain and their gene structures in vertebrates are diversified. In mammals, the clustered Pcdh family consists of three gene clusters: Pcdh -α, Pcdh -β, and Pcdh -γ. During brain development, this family is upregulated by neuronal differentiation, and Pcdh-α is then dramatically downregulated by myelination. Clustered Pcdh expression continues in the olfactory bulb, hippocampus, and cerebellum until adulthood. Structural analysis of the first cadherin domain of the Pcdh-α protein revealed it lacks the features that classical cadherins require for homophilic adhesiveness, but it contains Pcdh-specific loop structures. In Pcdh-α, an RGD motif on a specific loop structure binds β1-integrin. For gene expression, the gene clusters are regulated by multiple promoters and alternative cis splicing. At the single-cell level, several dozen Pcdh -α and -γ mRNA are regulated monoallelically, resulting in the combinatorial expression of distinct variable exons. The Pcdh-α and Pcdh-γ proteins also form oligomers, further increasing the molecular diversity at the cell surface. Thus, the unique features of the clustered Pcdh family may provide the molecular basis for generating individual cellular diversity and the complex neural circuitry of the brain.     

Transmembrane signalling by integrins

Recent work has shown that integrin receptors serve not only as structural receptors that connect the extracellular matrix to the cytoskeleton, but also as signalling receptors that regulate intracellular pH, intracellular free calcium, phosphorylation of proteins on tyrosine and inositol lipid turnover. The ability of extracellular matrix to influence growth, differentiation and other cell functions is very likely related to their effects on signaling pathways inside the cell.     

Function and interactions of integrins

Integrins are heterodimeric cell adhesion molecules that link the extracellular matrix to the cytoskeleton. The integrin family in man comprises 24 members, which are the result of different combinations of 1 of 18 alpha- and 1 of 8 beta-subunits. Alternative splicing of mRNA of some alpha- and beta-subunits and postranslational modifications of integrin subunits further increase the diversity of the integrin family. In their capacity as adhesion receptors that organize the cytoskeleton, integrins play an important role in controlling various steps in the signaling pathways that regulate processes as diverse as proliferation, differentiation, apoptosis, and cell migration. The intracellular signals that lead to these effects may be transduced via cytoplasmic components, which have been identified as integrin-binding proteins in yeast two-hybrid screens and which could mediate the coupling of integrins to intracellular signaling pathways. In this review an overview is given of the function and ligand-binding properties of integrins as well as of proteins that associate with integrins and may play a role in their signaling function.     

Spatial-temporal reorganization of activated integrins

Integrin receptors play important roles in cell adhesion and tumor metastasis. The coupling of mechanical sensing and biochemical ligation is known to collectively regulate the activation of integrin receptors. Recently, oligomerization of activated integrins has been considered as the primordial signature of cytoskeletal remodeling and the initiation of various downstream signals, such as focal and fibrillar adhesions. However, spatio-temporal reorganization of activated integrins and associated proteins remains poorly understood. Here, we summarized the recent discovery of sequential biophysical events of integrin activation during early adhesion formation. Using the cyclic Arg-Gly-Asp (RGD) peptide as a mobile ligand on supported lipid membranes, a series of previously unreported events were observed following integrin αvβ3 clustering and cell spreading, including a long-range lateral translocation of the integrin clusters. With initial clustering, localized actin polymerization occurred in a Src family kinase dependent manner. Clustering of liganded integrins recruits various adaptor proteins and serves as a reaction core for mechanobiological activities. In addition, there are future possibilities to investigate the role of other synergetic interactions with the activated integrin receptors.     

Spatial-temporal reorganization of activated integrins

Integrin receptors play important roles in cell adhesion and tumor metastasis. The coupling of mechanical sensing and biochemical ligation is known to collectively regulate the activation of integrin receptors. Recently, oligomerization of activated integrins has been considered as the primordial signature of cytoskeletal remodeling and the initiation of various downstream signals, such as focal and fibrillar adhesions. However, spatio-temporal reorganization of activated integrins and associated proteins remains poorly understood. Here, we summarized the recent discovery of sequential biophysical events of integrin activation during early adhesion formation. Using the cyclic Arg-Gly-Asp (RGD) peptide as a mobile ligand on supported lipid membranes, a series of previously unreported events were observed following integrin αvβ3 clustering and cell spreading, including a long-range lateral translocation of the integrin clusters. With initial clustering, localized actin polymerization occurred in a Src family kinase dependent manner. Clustering of liganded integrins recruits various adaptor proteins and serves as a reaction core for mechanobiological activities. In addition, there are future possibilities to investigate the role of other synergetic interactions with the activated integrin receptors.     

Clustered cases of paravaccinia in milkers

Clustered cases of a disease in men and cows firstly diagnosed as cowpox has been described. Clinical manifestation, epidemiology and laboratory diagnostics are presented. Virological and serological investigations of the specimens taken from sick persons and animals proved paravaccinia virus (genus Parapoxvirus) to be etiological agent of the illness. Cowpox virus (genus Orthopoxvirus) greatly differs from the latter by phenotypical markers. The disease in humans is called Milkers' modules, in cows--pseudocowpox. The disease is mostly benign and this is a reason why it does not attract sufficient attention of health personnel. Nevertheless this infection can cause a certain economical loss.     

Clustered sparsity and Poisson-gap sampling

Non-uniform sampling (NUS) is a popular way of reducing the amount of time taken by multidimensional NMR experiments. Among the various non-uniform sampling schemes that exist, the Poisson-gap (PG) schedules are particularly popular, especially when combined with compressed-sensing (CS) reconstruction of missing data points. However, the use of PG is based mainly on practical experience and has not, as yet, been explained in terms of CS theory. Moreover, an apparent contradiction exists between the reported effectiveness of PG and CS theory, which states that a “flat” pseudo-random generator is the best way to generate sampling schedules in order to reconstruct sparse spectra. In this paper we explain how, and in what situations, PG reveals its superior features in NMR spectroscopy. We support our theoretical considerations with simulations and analyses of experimental data from the Biological Magnetic Resonance Bank (BMRB). Our analyses reveal a previously unnoticed feature of many NMR spectra that explains the success of ”blue-noise” schedules, such as PG. We call this feature “clustered sparsity”. This refers to the fact that the peaks in NMR spectra are not just sparse but often form clusters in the indirect dimension, and PG is particularly suited to deal with such situations. Additionally, we discuss why denser sampling in the initial and final parts of the clustered signal may be useful.

     

Surface Plasmon Resonances of Clustered Nanoparticles

Linear clusters made by tightly connecting two or more metallic nanoparticles have new types of surface plasmon resonances as compared with isolated nanoparticles. These new resonances are sensitive to the size of the junction and to the number of interconnected particles and are described by eigenmodes of a boundary integral equation. This formulation allows effective separation of geometric and shape contribution from electric properties of the constituents. Results for particles covered by a thin shell are also provided highlighting ultrasensitive sensing applications. The present analysis sheds a new light on the interpretation of recent experiments.     

Regulation of ion channels by integrins

Ion channels are regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. Evidence for regulation of channels by tyrosine phosphorylation comes primarily from investigations of the effects of growth factors, which act through receptor tyrosine kinases. The purpose of the present work is to summarize evidence for the regulation of ion channels by integrins, through their downstream, nonreceptor tyrosine kinases. We review both direct and indirect evidence for this regulation, with particular emphasis on Ca2+-activated K+ and voltage-gated Ca2+ channels. We then discuss the critical roles that cytoskeletal, focal-adhesion, and channel-associated scaffolding proteins may play in localizing nonreceptor tyrosine kinases to the vicinity of ion channels. We conclude by speculating on the physiological significance of these regulatory pathways.     

Structural and mechanical functions of integrins

Integrins are ubiquitously expressed cell surface receptors that play a critical role in regulating the interaction between a cell and its microenvironment to control cell fate. These molecules are regulated either via their expression on the cell surface or through a unique bidirectional signalling mechanism. However, integrins are just the tip of the adhesome iceberg, initiating the assembly of a large range of adaptor and signalling proteins that mediate the structural and signalling functions of integrin. In this review, we summarise the structure of integrins and mechanisms by which integrin activation is controlled. The different adhesion structures formed by integrins are discussed, as well as the mechanical and structural roles integrins play during cell migration. As the function of integrin signalling can be quite varied based on cell type and context, an in depth understanding of these processes will aid our understanding of aberrant adhesion and migration, which is often associated with human pathologies such as cancer.     

Tenascin-C and integrins in cancer

Tenascin-C (TNC) is highly expressed in cancer tissues. Its cellular sources are cancer and stromal cells, including fibroblasts/myofibroblasts, and also vascular cells. TNC expressed in cancer tissues dominantly contains large splice variants. Deposition of the stroma promotes the epithelial-mesenchymal transition, proliferation, and migration of cancer cells. It also facilitates the formation of cancer stroma including desmoplasia and angiogenesis. Integrin receptors that mediate the signals of TNC have also been discussed.     

Adaptation Dynamics in Densely Clustered Chemoreceptors

In many sensory systems, transmembrane receptors are spatially organized in large clusters. Such arrangement may facilitate signal amplification and the integration of multiple stimuli. However, this organization likely also affects the kinetics of signaling since the cytoplasmic enzymes that modulate the activity of the receptors must localize to the cluster prior to receptor modification. Here we examine how these spatial considerations shape signaling dynamics at rest and in response to stimuli. As a model system, we use the chemotaxis pathway of Escherichia coli, a canonical system for the study of how organisms sense, respond, and adapt to environmental stimuli. In bacterial chemotaxis, adaptation is mediated by two enzymes that localize to the clustered receptors and modulate their activity through methylation-demethylation. Using a novel stochastic simulation, we show that distributive receptor methylation is necessary for successful adaptation to stimulus and also leads to large fluctuations in receptor activity in the steady state. These fluctuations arise from noise in the number of localized enzymes combined with saturated modification kinetics between the localized enzymes and the receptor substrate. An analytical model explains how saturated enzyme kinetics and large fluctuations can coexist with an adapted state robust to variation in the expression levels of the pathway constituents, a key requirement to ensure the functionality of individual cells within a population. This contrasts with the well-mixed covalent modification system studied by Goldbeter and Koshland in which mean activity becomes ultrasensitive to protein abundances when the enzymes operate at saturation. Large fluctuations in receptor activity have been quantified experimentally and may benefit the cell by enhancing its ability to explore empty environments and track shallow nutrient gradients. Here we clarify the mechanistic relationship of these large fluctuations to well-studied aspects of the chemotaxis system, precise adaptation and functional robustness.