The insulin receptor substrate-1: a biomarker for cancer?

This review focuses on IRS-1 and the evidence of its role in cell transformation. The literature strongly suggests that IRS-1 should be considered a biomaker for cancers susceptible to IGF-IR targeting. In addition, I would like to propose that IRS-1 may have a more general role in cancer, and could be considered as a protein having the opposite effect of tumor suppressors, a sort of anti-p53 molecule.     

In search of membrane receptors for microtubule-based motors - is kinectin a kinesin receptor?

The past few years have seen an explosion in the number of molecular motors reported in the literature. By us the energy of hydrolysis, these motors move various organelles along cytoskeletal 'tracks' within the cell. It is thought that some of the specificity of movement resides in receptors on the surface of the cargo organelles, but, in general, little is known about these molecules. In this article, Janis Burkhardt discusses the evidence that the protein kinectin serves as a membrane receptor for kinesin, and describes how motor-receptor proteins may interact with other components of the motility machinery to generate regulated movement of membrane organelles.     

The changing world of G protein-coupled receptors: from monomers to dimers and receptor mosaics with allosteric receptor–receptor interactions

Based on indications of direct physical interactions between neuropeptide and monoamine receptors in the early 1980s, the term receptor–receptor interactions was introduced and later on the term receptor heteromerization in the early 1990s. Allosteric mechanisms allow an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly via receptor–receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. Stable heteromers of Class A receptors may be formed that involve strong high energy arginine–phosphate electrostatic interactions. These receptor–receptor interactions markedly increase the repertoire of GPCR recognition, signaling and trafficking in which the minimal signaling unit in the GPCR homomers appears to be one receptor and one G protein. GPCR homomers and GPCR assemblies are not isolated but also directly interact with other proteins to form horizontal molecular networks at the plasma membrane.     

The NAADP receptor: new receptors or new regulation?

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent calcium mobilizing messenger yet discovered. Its action has now been reported in a large number of cell types from a diverse array of organisms, and in some cases linked to the transduction of specific cellular stimuli. However, what is controversial is the nature of its target calcium release channel, as well as the subcellular localization of its receptor. Some have proposed that NAADP activates a novel calcium release channel distinct from the two major classes of channels known, the inositol trisphosphate receptors and ryanodine receptors. However, others have suggested that it acts in a novel way to regulate a known calcium release channel, the ryanodine receptor.     

The OXE receptor: a new therapeutic approach for asthma?

The eicosanoid 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) has recently been identified as the ligand for the oxoeicosanoid (OXE) receptor. In vitro and in vivo studies have suggested that 5-oxo-ETE has a role in the asthmatic inflammatory response and it has been shown to stimulate eosinophil migration to the airways. New data suggest that eosinophils have an important role in the pathogenesis of asthma, being required for mucus accumulation, airway hyperresponsiveness and remodelling of the airways. However, there are several mediators that can stimulate the recruitment of eosinophils to the airways and the development of antagonists against the OXE receptor is required to evaluate the potential of the OXE receptor as a new therapeutic approach for asthma.     

The HDL receptor SR-BI: a new therapeutic target for atherosclerosis?

Although high-density lipoprotein (HDL) metabolism is a crucial process for cholesterol homeostasis and coronary heart disease, therapeutic approaches for selective modification of plasma HDL levels are not currently available. The discovery of well-defined cell-surface HDL receptors should provide new avenues for treatment of atherosclerotic cardiovascular disease. In fact, SR-BI, a recently identified receptor for selective HDL cholesterol uptake, is relevant for physiological processes (for example, HDL metabolism, steroidogenesis and biliary cholesterol secretion) and pathophysiological conditions (for example, atherosclerosis) in animal models. If SR-BI has similar activities in humans, it might represent a new therapeutic target for atherosclerosis.     

Ryanodine receptor resolution revolution: Implications for InsP3 receptors?

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The tetrameric α-helical membrane protein GlpF unfolds via a dimeric folding intermediate

Many membrane proteins appear to be present and functional in higher-order oligomeric states. While few studies have analyzed the thermodynamic stability of α-helical transmembrane (TM) proteins under equilibrium conditions in the past, oligomerization of larger polytopic monomers has essentially not yet been studied. However, it is vital to study the folding of oligomeric membrane proteins to improve our understanding of the general mechanisms and pathways of TM protein folding. To investigate the folding and stability of the aquaglyceroporin GlpF from Escherichia coli, unfolding of the protein in mixed micelles was monitored by steady-state fluorescence and circular dichroism spectroscopy as well as by seminative sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. On the basis of our results, it appears most likely that GlpF unfolds in a two-step process, involving the equilibrium of tetrameric, dimeric, and monomeric GlpF species. A kinetic analysis also indicates an intermediate along the kinetic GlpF unfolding pathway, and thus, two phases are involved in GlpF unfolding. While three-state unfolding pathways and a dimeric folding intermediate are not uncommon for water-soluble proteins, a stable (un)folding intermediate with a decreased oligomeric structure has not been detected or reported for any α-helical membrane protein.     

The phosphatidylserine receptor: a crucial molecular switch?

The uptake and removal of necrotic or lysed cells involves inflammation and an immune response, due in part to processes that involve members of the collectin family, surface calreticulin and CD91. Clearance of apoptotic cells, by contrast, does not induce either inflammation or immunity. Could the phosphatidylserine receptor be the molecular switch that determines what the outcome will be?     

Transgenic rescue for characterizing orphan receptors: a review of δ2 glutamate receptor

Even though the genomes of several major species have been sequenced, many orphan receptors with unknown ligands and mechanisms of action remain in the CNS. The 2 glutamate receptor (GluR2) is one of such receptors expressed predominantly in the cerebellar Purkinje cells. On the basis of amino acid similarity, it belongs to ionotropic glutamate receptor (iGluR) family, which mediates fast excitatory neurotransmission in the mammalian CNS. Although its null-mutant mice show prominent motor discoordination, the mechanisms by which GluR2 participates in the cerebellar functions have been unclear. To gain insight into GluR2s mechanisms, we recently generated mice that express either a wild-type or a mutant GluR2 transgene, in which the conserved arginine in GluR2s N-terminal putative ligand-binding motif was disrupted. By breeding these transgenic mice onto a GluR2^–/– background, we obtained two transgenic rescue lines. Surprisingly, the mutant GluR2 transgene was as effective as the wild-type GluR2 in rescuing the GluR2-null mice. As the disrupted arginine residue is highly conserved from ancestral bacterial periplasmic amino acid-binding proteins to mammalian iGluRs, we propose that GluR2 may not require glutamate-like amino acids and may function in an unconventional manner. This transgenic rescue approach to investigating orphan receptors is a relatively easy but powerful method when a knockout mouse with a distinct phenotype is already available. The advantages and limitations of this approach, together with certain cautions in interpreting the resulting data, are discussed in this review.     

Plexins, semaphorins, and scatter factor receptors: a common root for cell guidance signals?

Semaphorins, the plexin family of semaphorin receptors, and scatter factor receptors share evolutionarily conserved protein modules, such as the semaphorin domain and Met Related Sequences (MRS). All these proteins also have in common a role in mediating cell guidance cues. During development, scatter factor receptors control cell migration, epithelial tubulogenesis, and neurite extension. Semaphorins and their receptors are known signals for axon guidance; they are also suspected to regulate developmental processes involving cell migration and morphogenesis, and have been implicated in immune function and tumor progression. Scatter factors and secreted semaphorins are diffusible ligands, whereas membrane-bound semaphorins signal by cell-cell interaction. Cell guidance control by semaphorins requires plexins, alone or in a receptor complex with neuropilins. Semaphorins, besides their role in axon guidance, are expected to have multiple functions in morphogenesis and tissue remodeling by mediating cell-repelling cues through plexin receptors.     

Wza: a new structural paradigm for outer membrane secretory proteins?

Gram-negative bacteria need to be able to transport a large variety of macromolecules across their outer membranes. In Escherichia coli, the passage of the group 1 capsular polysaccharide is mediated by an integral outer membrane protein, Wza. The crystal structure of Wza, determined recently, reveals a novel transmembrane alpha-helical barrel and a large central cavity within the core of the vase-shaped protein complex. The structure has similarities with that of the secretin protein, PilQ, which mediates the transition of type IV pili across the outer membrane. We propose that the large internal chamber, which can accommodate the secreted assembled macromolecule, is likely to be a common feature found in other outer membrane proteins involved in secretion processes.     

Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system?

One of the many functions of liver peroxisomes is the beta-oxidation of long-chain fatty acids. It is essential for the continuation of peroxisomal beta-oxidation that a redox shuttle system exist across the peroxisomal membrane to reoxidize NADH. We propose that this redox shuttle system consists of a substrate cycle between lactate and pyruvate. Here we present evidence that purified peroxisomal membranes contain both monocarboxylate transporter 1 (MCT 1) and MCT 2 and that along with peroxisomal lactate dehydrogenase (pLDH) form a Peroxisomal Lactate Shuttle. Peroxisomal beta-oxidation was greatly stimulated by the addition of pyruvate and this increase was partially inhibited by the addition of the MCT blocker alpha-cyano-4-hydroxycinnamate (CINN). We also found that peroxisomes generated lactate in the presence of pyruvate. Together these data provide compelling that the Peroxisome Lactate Shuttle helps maintain organelle redox and the proper functioning of peroxisomal beta-oxidation.     

Angiogenesis and rhodopsin-like receptors: a role for N-terminal acidic residues?

Numerous rhodopsin-like G-protein coupling receptors induce or inhibit angiogenesis. The active human receptors include several chemokine receptors, apelin APJ receptor, neuropeptide Y Y2 receptor, Duffy antigen, and herpes virus-8 receptor. A common and striking feature of these receptors is the large fraction (up to 42%) of residues with anionic sidechains (Asp, Glu, and benzene anions Tyr, Trp, and Phe) in the N-terminal extracellular domain. These residues (which are frequently clustered) can assist the binding of ligand peptides, but should also support interactions that help tubular arraying of cells, e.g., via cationic bridges and/or hydrogen bonding with cell-connecting receptors such as integrins, or with proteins of the extracellular matrix.