Eph-related receptors and their ligands: mediators of contact dependent cell interactions

 Recent studies of the large families of Eph-related receptor tyrosine kinases and their ligands suggest that they have key roles in embryonic development. These receptors mediate cell contact dependent signalling by binding to membrane-bound ligands, and certain ligands may themselves transduce signals. Functional studies indicate that in a number of tissues the receptors and ligands are expressed in complementary domains and mediate repulsive interactions that restrict cell and axon migration. In addition, they can also stimulate cell migration. Eph-related receptors and their ligands are therefore mediators of cell interactions required for tissue patterning and neuronal pathfinding during development. The potential clinical implications of these findings are discussed. Received: 24 January 1997 / Accepted: 17 March 1997     

Hormone receptors.

This article reviews the literature on hormone receptors and presents information on the following broad topics: 1) steroid hormone receptors (vs. cytoplasmic); 2) thyroid hormone receptors; 3) catecholamine and peptide hormone receptors; 4) internalization of polypeptide and catecholamine hormone-receptor complexes; 5) affinity (as the basis for discrimination of hormonal signals); 6) binding curves and Scatchard plots; 7) nonspecific and nonreceptor binding; 8) curvilinear Scatchard plots, indicating multiple sites and negative cooperativity; 9) definition of class of hormone action and hormonal occupancy of several classes of receptors; 10) receptor-response relation (close coupling and spare receptors); 11) regulation of receptors (a mechanism important for control of cellular sensitivity to hormones); 12) hormone antagonists and partial agonists and antagonists; 13) receptors and the clinical evaluation of hormone and drug levels; and 14) receptor-related diseases. Throughout the literature, identification of hormone-binding sites as receptors has relied mainly on correlations between hormone binding and biologic effects, on genetic and other studies where loss of (or changes in) receptors are associated with altered hormone responsiveness, and on the finding that receptor binding by anti-receptor antibodies or antagonists attentuates or abolishes the hormone responses.     

Exploring the role of sex steroids through studies of receptor deficient mice

Decades of study have described a number roles fulfilled by the steroid hormones and their respective receptors in sexual differentiation and development, reproductive function and behavior, and more recently in the function and maintenance of non-reproductive organ systems, such as skeletal muscle, bone and coronary tissues. The biological effects of the steroid hormones are believed to be mediated in part by specific receptor proteins that demonstrated great specificity for their respective steroid ligands. Much of the experimental research of the functions of the sex steroid receptors has depended upon in vitro systems as well as in vivo methods that require surgical castration or the pharmacological administration of hormone antagonists. However, recently developed techniques that allow for manipulation of the mouse genome have been utilized to generate transgenic animals that lack functional estrogen or progesterone receptors. These transgenic animals, combined with the naturally existing Tfm mice which lack functional androgen receptor, now provide in vivo models for further study of the various actions of the sex steroids and their receptors. This review attempts to describe and compare the various phenotypes that result in each of these lines of mice, with emphasis on the development and function of the reproductive systems as well as reproductive behavior. Received: 19 June 1997 / Accepted: 25 September 1997     

Membrane oestrogen receptor α signalling to cell functions

Conservation of steroid hormone action outside the nucleus occurs from plants that make brassinosteroids to higher metazoans (primates). In plants, steroid hormone action occurs when the brassinosteroids bind a membrane tyrosine kinase receptor. Ligated receptors for all sex steroids exist at the plasma membrane and rapidly signal through G proteins to second messengers including calcium, cAMP and cGMP, activating proximal and more distal kinases. These signal cascades impact many functions of steroid hormones, responsible for the biological actions of these molecules. Support also exists for membrane-localized receptors of other members of the steroid superfamily, responding to glucocorticoids, mineralocorticoids, thyroid hormone, and vitamin D. The nature of these receptors is in some cases unclear. Steroid receptors also exist in discrete cytoplasmic organelles, most notably the mitochondria, although the functions of these receptors are poorly understood. In this review, I highlight the essential elements of the membrane oestrogen receptor α, noting where conserved aspects exist for other steroid receptors.     

Effect of active and passive immunization of male and female rats with a recombinantly expressed bonnet monkey pituitary GnRH receptor fragment

Gonadotropin releasing hormone (GnRH) exerts its action by binding to the specific receptor which belongs to the family of G-protein coupled receptors that are characterized by the presence of seven transmembrane domains linked together by extracellular and intracellular loops. A fragment of the pituitary receptor of the bonnet monkey (Macaca radiata) corresponding to amino acids 164-266 was cloned and expressed in Escherichia coli. This was used to raise antibodies to the receptor in rabbits. Active and passive immunization studies in both male and female rats were carried out using, both the 'overexpressed' fragment, as well as antibodies raised to the receptor fragment. Both active, as well as passive immunization in the male rats brought about an agonistic effect in terms of increase in serum LH level, as well as increase in serum and testicular testosterone levels. However, in the female rats, active immunization with the receptor fragment did not have any effect on the gonadal steroid levels but had a selective effect on the uterine morphology.     

Molecular understanding of hematopoietin/cytokine receptor signaling defects in hematopoietic disorders

 Hematopoietic growth factors (HGFs) act on the hematopoietic cells via binding to specific cell surface receptors. Many HGF receptors have certain common structural features and have therefore been grouped in the superfamily of hematopoietin or cytokine receptors, also referred to as the class I receptor superfamily [1, 2]. Activation of these receptors by their cognate growth factors is mediated through the formation of dimeric or oligomeric complexes of receptor structures. Some HGF receptors are composed of heteromeric complexes, comprising two or three different receptor chains. For instance, this is the case for receptors of interleukins 2, 3, and 5 and granulocyte-macrophage colony-stimulating factor [3]. Other receptor structures, for example, those of granulocyte colony-stimulating factor and erythropoietin, form homodimeric complexes upon growth factor binding [2, 4]. This brief overview begins with an introduction of the major principles of HGF receptor signaling; this is followed by a discussion of the consequences of HGF receptor signaling defects for the development of disorders of the hematopoietic system and the presentation of clinical examples of such diseases. Received: 1 February 1997 / Accepted: 5 May 1997     

Neutralising Antibodies to the Granulocyte Colony-stimulating Factor Receptor Recognise both the Immunoglobulin-like Domain and the Cytokine Receptor Homologous Domain

Abstract

To define regions of the granulocyte colony-stimulating factor (G-CSF) receptor that are important for ligand binding, neutralising monoclonal antibodies to the human receptor have been produced. Eleven antibodies recognised six different receptor epitopes. Antibodies from three of the epitope groups were able to detect the receptor by western blotting but did not inhibit G-CSF binding. The other three antibody groups inhibited G-CSF binding either completely (groups 1 and 2) or partially (group 3). All the antibodies inhibited proliferation of BA/F3 cells expressing the G-CSF receptor to varying extents. By using human-murine chimeric receptors, the binding sites of the antibodies were mapped to the immunoglobulin-like domain (groups 1 and 3), the cytokine receptor homologous domain (group 2) or the fibronectin type III domains (groups 4 to 6). These results show that the immunoglobulin-like and cytokine receptor homologous domains of the receptor are important for ligand binding and subsequent signalling.     

Lectin binding and steroid receptors in human breast carcinomas

A series of breast carcinomas of known steroid receptor status have been examined for evidence of binding of the lectins peanut agglutinin, soy bean agglutinin and wheat germ agglutinin. Correlations were found between oestrogen receptor status and reactivity of carcinomas to peanut agglutinin and soy bean agglutinin but these were not absolute. Wheat germ agglutinin binding was unrelated to the presence of oestrogen receptors. No relationship was evident between progestogen receptors and the binding of any lectin. It therefore seems unlikely that lectin histochemistry can replace steroid receptors as markers of hormone dependence in breast carcinomas.     

Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action

Steroid target tissues regulate the local level of steroid hormone that can bind and trans-activate nuclear receptors (a process known as intracrine modulation). This pre-receptor regulation can be achieved by hydroxysteroid dehydrogenases (HSDs). For each sex hormone there is a pair of HSD isoforms which act either as reductases or oxidases to convert potent steroid hormones into their cognate inactive metabolites, or vice-versa. In this manner, HSDs can function as molecular switches to regulate steroid hormone action. Because these HSDs show tissue-specific expression, inhibitors of these enzymes are predicted to cause tissue-specific responses to steroid hormones. These inhibitors would represent a new class of therapeutics called 'selective intracrine modulators' (SIMs). SIMs are expected to have the same tissue-specific effects as selective steroid receptor modulators but a different mode of action as their effects are enzyme- and not receptor-mediated. HSDs responsible for these interconversions belong to two protein superfamilies: the short-chain dehydrogenases/reductases; and the aldo-keto reductases. Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad-based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target.     

Membrane receptors for vitamin D metabolites

Membrane-initiated signaling by steroid hormones is now widely accepted. Current debate is centered upon which protein moieties act as membrane-associated receptors. In this review, we consider evidence for the classical vitamin D receptor (VDR) in this role, as well as the more recently identified 1,25D3-MARRS (membrane-associated, rapid response steroid binding) receptor, also known as ERp57/GRp58. The structure of the 1,25D3-MARRS receptor is discussed, with emphasis on two thioredoxin domains that promote dimerization and ligand binding. We then summarize recent studies on a 24,25(OH)2D3 binding protein--catalase--and how ligand-induced decreases in enzymatic activity produce increased reactive oxygen species that target both the 1,25D3-MARRS receptor--but not the VDR--and the protein kinase C signaling pathway. Finally, we briefly discuss the available literature suggesting that the metabolite 25(OH)D3 may also be biologically active.     

"Monovalent" ligands that trigger TLR-4 and TCR are not necessarily truly monovalent

Cell surface receptors mediate many cellular responses in health and disease. Recent progress in our understanding of how ligand binding to the extracellular domains of receptors triggers intracellular signaling has underlined the role of ligand-promoted receptor clustering following by oligomerization of the cytoplasmic signaling domains. The clustering suggests the requirement of ligand multivalency and is especially important for triggering receptors involved in innate and adaptive immune responses. However, although numerous studies have established that multivalent, but not monovalent, ligands induce receptor-mediated signal transduction, considerable uncertainty still remains. Here, I hypothesize that "monovalent" ligands that have been reported to trigger immune receptors in vitro are not necessarily truly monovalent. This is illustrated by focusing on studies of signal transduction by toll-like receptor-4 and T cell receptor. By generalizing this concept to a variety of lipid and protein ligands, one would propose an alternative interpretation of apparent ligand monovalency in other receptor activation studies as well.     

Klinische Relevanz von Glucocorticoid-Rezeptoren für die Behandlung lymphoider Neoplasien

Summary A generalized view on the mechanism of steroid hormone action is presented with special emphasis on glucocorticoids and their lymphocytolytic effects. The present knowledge on the structure and function of glucocorticoid receptors is reviewed. Following hormone binding, the receptor complex is activated to a form which is able to interact with chromatin or DNA. Several types of receptor mutants have been obtained in an animal cell culture system which allows selection of cell variants. The biochemical analysis of these mutants helped to establish a domain model of receptor structure. The quantitative effect of receptor numbers and hormone activity on lymphocytolysis is described in a cell culture model system and the results are discussed in view of the rational treatment of lymphoid neoplasia with glucocorticoids. The clinical experience with glucocorticoids alone and in combination therapy with cytostatic drugs is summarized. Our special emphasis is on acute lymphoblastic leukemia and malignant lymphoma as patients with these diseases can now be treated with remarkable success rates.