Lysinuric protein intolerance mutation is not expressed in the plasma membrane of erythrocytes

Summary We measured mediated fluxes of l-lysine and l-ornithine across the plasma membrane of erythrocytes from control subjects and patients homozygous for the lysinuric protein intolerance (LPI) mutation. We found no differences in net uptake or efflux of cationic amino acids in control and LPI cells, contrary to our findings in cultured skin fribroblasts. We conclude that expression of the LPI (y⁺) transport system for cationic amino acids varies between tissues and that measurements of fluxes in erythrocytes cannot be used for diagnosis of LPI.     

Alpha 1 anti-trypsin: one protein, many functions

α-1 anti-trypsin (AAT) is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant. Systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema. Considered the prototypic serpin, the emphysema observed in patients with AATD, consisting of progressive destruction of the alveoli and small airway structures, formed the basis of the protease/anti-protease imbalance theory of chronic obstructive pulmonary disease (COPD). Over the past decade, however, investigations of AATD have described multiple functions of AAT beyond those generally attributed to its antiprotease activity. Evidence now suggests that AAT plays an important role in modulating immunity, inflammation, proteostasis, apoptosis, and possibly cellular senescence programs. When integrated in vivo, these processes contribute to the lung maintenance program which preserves the lung despite a constant bombardment by damage associated molecular patterns (DAMPs) and/or pathogenassociated molecular patterns (PAMPs) initiated by cigarette smoke, pollutants, or infections. In this review, we discuss the clinical aspects of AATD as they pertain to emphysema; including similarities and differences to cigarette smoke-induced emphysema. Examining the lung maintenance program, we next consider the multiple mechanisms of airspace destruction and explore the role AATD contributes. Finally, we consider the data regarding treatment of AATD, including AAT supplementation and its current limitations, and suggest further avenues of research informed by the multiple functions of AAT.     

Neogenin: one receptor, many functions

Neogenin is a multifunctional transmembrane receptor belonging to the immunoglobulin superfamily. It displays identical secondary structure to deleted in colorectal cancer (DCC), a netrin receptor that is involved in axon guidance and cell survival. Like DCC, neogenin is able to transduce signals elicited by netrin. These neogenin-netrin interactions have been implicated in tissue morphogenesis, angiogenesis, myoblast differentiation and most recently in axon guidance. Neogenin is also a receptor for repulsive guidance molecule, a glycosylphosphatidylinositol-linked protein involved in neuronal differentiation, apoptosis and repulsive axon guidance. Numerous studies have been started to elucidate the in vivo functions of neogenin, and its role in multiple aspects of development and homeostasis.     

Resveratrol: one molecule, many targets

Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources. In recent years, the interest in this molecule has increased exponentially following the major findings that resveratrol (i) is shown to be chemopreventive in some cancer models, (ii) is cardioprotective, and (iii) has positive effects on several aspects of metabolism, leading to increased lifespan in all the metazoan models tested thus far, including small mammals. Such remarkable properties have elicited a vast interest towards the identification of target proteins of resveratrol and have led to the identification of enzymes inhibited by resveratrol and others whose activation is enhanced. In the vast majority of cases, resveratrol displays inhibitory/activatory effects in the micromolar range, which is potentially attainable pharmacologically, although targets with affinities in the nanomolar range have also been reported. Here, we provide an overview of the various classes of enzymes known to be inhibited (or activated) by resveratrol. It appears that resveratrol, as a pharmacological agent, has a wide spectrum of targets. The biological activities of resveratrol may thus be dependent on its simultaneous activity on multiple molecular targets.     

BS-cadherin in the colonial urochordate Botryllus schlosseri: one protein, many functions

Botryllus schlosseri is a colonial urochordate composed of coexisting modules of three asexually derived generations, the zooids and two cohorts of buds, each at disparate developmental stage. Functional zooids are replaced weekly by the older generation of buds through a highly synchronized developmental cycle called blastogenesis (which is, in turn, divided into four major stages, A to D). In this study, we examined the mode of expression of BS-cadherin, a 130-kDa transmembrane protein isolated from this species, during blastogenesis. BS-Cadherin is expressed extensively in internal organs of developing buds, embryos, ampullae and, briefly, in the digestive system of zooids at early blastogenic stage D (in contrast to low mRNA expression at this stage). In vitro trypsin assays on single-cell suspensions prepared from blastogenic stage D zooids, confirmed that BS-cadherin protein is expressed on cell surfaces and is, therefore, functional. BS-Cadherin expression is also upregulated in response to various stress conditions, such as oxidative stress, injury and allorecognition. It plays an important role in colony morphogenesis, because siRNA knockdown during D/A blastogenic transition causes chaotic colonial structures and disrupts oocytes homing onto their bud niches. These results reveal that BS-cadherin protein functions are exerted through a specific spatiotemporal pattern and fluctuating expression levels, in both development/regular homeostasis and in response to various stress conditions.     

Cancer proteomics: many technologies,one goal

A major goal of the National Cancer Institute is to alleviate patient pain, suffering and death associated with cancer by the year 2015. This goal does not insinuate a cure for cancer, but rather the development of diagnostics and therapeutics that will eventually decrease cancer morbidity and mortality. A part of meeting this goal is to leverage the enormous data-gathering capabilities of proteomic technologies to discover disease-specific biomarkers in serum, plasma, urine, tissues and other biologic samples. The rapid advance in available technologies that have been spurred by the -omics era, has enabled biologic samples to be surveyed for biomarkers in ways never before possible. However, it is not yet clear which specific technologies will be the most successful. Therefore, proteomic laboratories within the National Cancer Institute are taking a multipronged approach to identify disease-specific biomarkers. This review discusses some of these approaches in their context of meeting the National Cancer Institute’s 2015 goal.     

Cancer proteomics: many technologies, one goal

A major goal of the National Cancer Institute is to alleviate patient pain, suffering and death associated with cancer by the year 2015. This goal does not insinuate a cure for cancer, but rather the development of diagnostics and therapeutics that will eventually decrease cancer morbidity and mortality. A part of meeting this goal is to leverage the enormous data-gathering capabilities of proteomic technologies to discover disease-specific biomarkers in serum, plasma, urine, tissues and other biologic samples. The rapid advance in available technologies that have been spurred by the -omics era, has enabled biologic samples to be surveyed for biomarkers in ways never before possible. However, it is not yet clear which specific technologies will be the most successful. Therefore, proteomic laboratories within the National Cancer Institute are taking a multipronged approach to identify disease-specific biomarkers. This review discusses some of these approaches in their context of meeting the National Cancer Institute's 2015 goal.     

Molecular motors: from one motor many tails to one motor many tales

Kinesin and dynein molecular motor proteins generate the movement of a wide variety of materials in cells. Such movements are crucial for many different cellular and developmental functions, including organelle movement, localization of developmental determinants, mitosis, meiosis and possibly long-range signaling in neurons. Kinesins that control the dynamics of microtubules have also been discovered. Recent work has begun to identify processes in which defective molecular motor function can cause human disease.     

Cellular signal processing: out of one, many

Cells can make fate decisions in response to information from the environment. In this issue of Molecular Cell, Chen et al. (2012) describe how the design of a signal-processing pathway allows a homogenous population of cells to display diverse responses to uniform growth factor cues.     

Protein trafficking to plastids: one theme, many variations

Plastids are a diverse group of essential organelles in plants that include chloroplasts. The biogenesis and maintenance of these organelles relies on the import of thousands of nucleus-encoded proteins. The complexity of plastid structure has resulted in the evolution of at least four general import pathways that target proteins into and across the double membrane of the plastid envelope. Several of these pathways can be further divided into specialty pathways that mediate and regulate the import of specific classes of proteins. The co-ordination of import by these specialized pathways with changes in gene expression is critical for plastid and plant development. Moreover, protein import is acutely regulated in response to physiological and metabolic changes within the cell. In the present review we summarize the current knowledge of the mechanism of import via these pathways and highlight the regulatory mechanisms that integrate the plastid protein-trafficking pathways with the developmental and metabolic state of the plant.     

The tumor protein D52 family: many pieces, many puzzles

Tumor protein D52-like proteins are small coiled-coil motif bearing proteins which are conserved from lower organisms to human. The founding member of the family, human D52, has principally attracted research interest due to its frequent overexpression in cancer, often in association with D52 gene amplification. This review summarises published literature concerning this protein family since their discovery, which is highlighting an increasing diversity of functions for D52-like proteins. This in turn highlights a need for more comparative functional analyses, to determine which functions are conserved and which may be isoform-specific. This knowledge will be crucial for any future manipulation of D52 function in human disease, including cancer.