Annual Review of Cell and Developmental Biology - Volume 12, 1996

Each organelle of the secretory pathway is required to selectively allow transit of newly synthesized secretory and plasma membrane proteins and also to maintain a unique set of resident proteins that define its structural and functional properties. In the case of the endoplasmic reticulum (ER), residency is achieved in two ways: (a) prevention of residents from entering newly forming transport vesicles and (b) retrieval of those residents that escape. The latter mechanism is directed by discrete retrieval motifs: Soluble proteins have a H/KDEL sequence at their carboxy-terminus; membrane proteins have a dibasic motif, either di-lysine or di-arginine, located close to the terminus of their cytoplasmic domain. Recently it was found that di-lysine motifs bind the complex of cytosolic coat proteins, COP I, and that this interaction functions in the retrieval of proteins from the Golgi to the ER. Also discussed are the potential roles this interaction may have in vesicular trafficking.

The aryl hydrocarbon (Ah) receptor has occupied the attention of toxicologists for over two decades. Interest arose from the early observation that this soluble protein played key roles in the adaptive metabolic response to polycyclic aromatic hydrocarbons and in the toxic mechanism of halogenated dioxins and dibenzofurans. More recent investigations have provided a fairly clear picture of the primary adaptive signaling pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity studies have provided an understanding of the pharmacology of this receptor; recombinant DNA approaches have identified the enhancer sequences through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized mechanism of dioxin toxicity. In addition, it is hoped that this information can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological responses to an array of environmental stimuli.

The cytokine receptor superfamily is characterized by structural motifs in the exoplasmic domain and by the absence of catalytic activity in the cytosolic segment. Activated by ligand-triggered multimerization, these receptors in turn activate a number of cytosolic signal transduction proteins, including protein tyrosine kinases and phosphatases, and affect an array of cellular functions that include proliferation and differentiation. Molecular study of these receptors is revealing the roles they play in the control of normal hematopoiesis and in the development of disease.

Three of the most important questions concerning actin function are: (a) How does actin structure relate to actin function? (b) How does each of the numerous proteins that interact with actin contribute to actin cytoskeleton function in vivo? (c) How are the activities of these proteins regulated? Powerful molecular genetics combined with well-established biochemical techniques make the yeast Saccharomyces cerevisiae an ideal organism for studies aimed at answering these questions.

The protein sequences and biochemical properties of actin and its interacting proteins and the pathways that regulate these interactions all appear to be conserved, indicating that principles elucidated from studies in yeast will apply to all eukaryotes. In this review, we highlight advances in our general understanding of actin properties, interactions with other proteins, and regulation of the actin cytoskeleton, derived from studies in the budding yeast S. cerevisiae.

Recent studies on the development of the legs and wings of Drosophila have led to the conclusion that insect limb development is controlled by localized pattern organizing centers, analogous to those identified in vertebrate embryos. Genetic analysis has defined the events that lead to the formation of these organizing centers and has led to the identification of gene products that mediate organizer function. The possibility of homology between vertebrate and insect limbs is considered in light of recently reported similarities in patterns of gene expression and function.

Receptors for the Fc domain of immunoglobulins play an important role in immune defense. There are two well-defined functional classes of mammalian receptors. One class of receptors transports immunoglobulins across epithelial tissues to their main sites of action. This class includes the neonatal Fc receptor (FcRn), which transports immunoglobulin G (IgG), and the polymeric immunoglobulin receptor (pIgR), which transports immunoglobulin A (IgA) and immunoglobulin M (IgM). Another class of receptors present on the surfaces of effector cells triggers various biological responses upon binding antibody-antigen complexes. Of these, the IgG receptors (FcγR) and immunoglobulin E (IgE) receptors (FcϵR) are the best characterized. The biological responses elicited include antibody-dependent, cell-mediated cytotoxicity, phagocytosis, release of inflammatory mediators, and regulation of lymphocyte proliferation and differentiation. We summarize the current knowledge of the structures and functions of FcRn, pIgR, and the FcγR and FcϵRI proteins, concentrating on the interactions of the extracellular portions of these receptors with immunoglobulins.

A taxonomically diverse group of bacterial pathogens have evolved a variety of strategies to subvert host-cellular functions to their advantage. This often involves two-way biochemical interactions leading to responses in both the pathogen and host cell. Central to this interaction is the function of a specialized protein secretion system that directs the export and/or translocation into the host cells of a number of bacterial proteins that can induce or interfere with host-cell signal transduction pathways. The understanding of these bacterial/host-cell interactions will not only lead to novel therapeutic approaches but will also result in a better understanding of a variety of basic aspects of cell physiology and immunology.

Leaves are produced repeatedly from the shoot apical meristem of plants. Molecular and cellular evidence show that identity of the leaf and its parts is acquired progressively and that the underlying process changes as the leaf matures. The relative importance of cell lineage compared with a position-dependent model for specifying cell fates is discussed.

In this chapter, we review the structure and composition of interphase and mitotic chromosomes. We discuss how these observations support the model that mitotic condensation is a deterministic process leading to the invariant folding of a given chromosome. The structural studies have also placed constraints on the mechanism of condensation and defined several activities needed to mediate condensation. In the context of these activities and structural information, we present our current understanding of the role of cis sites, histones, topoisomerase II, and SMC proteins in condensation. We conclude by using our current knowledge of mitotic condensation to address the differences in chromosome condensation observed from bacteria to humans and to explore the relevance of this process to other processes such as gene expression.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that belong to the steroid/thyroid/retinoic acid receptor superfamily. All their characterized target genes encode proteins that participate in lipid homeostasis. The recent finding that antidiabetic thiazolidinediones and adipogenic prostanoids are ligands of one of the PPARs reveals a novel signaling pathway that directly links these compounds to processes involved in glucose homeostasis and lipid metabolism including adipocyte differentiation. A detailed understanding of this pathway could designate PPARs as targets for the development of novel efficient treatments for several metabolic disorders.

More than 100 years have passed since Weismann first recognized the role of germ cells in the continuity of a species. Today, it remains unclear how a germ cell is initially set aside from somatic cells and how it chooses its unique developmental path. In this review, we address various aspects of germ cell development in Drosophila, such as germ cell determination, germ cell migration, gonad formation, sex determination, and gametogenesis. Many aspects of germ cell development, including the morphology of germ cells, their migratory behavior, as well as the processes of gonad formation and gametogenesis, show striking similarities among organisms. Considering the conservation of factors that regulate somatic development, it is likely that some aspects of germ cell development are shared not only on a morphological but also on the molecular level between Drosophila and other organisms.

The Toll-Dorsal pathway in Drosophila and the interleukin-1 receptor (IL-1R)-NF-κB pathway in mammals are homologous signal transduction pathways that mediate several different biological responses. In Drosophila, genetic analysis of dorsal-ventral patterning of the embryo has defined the series of genes that mediate the Toll-Dorsal pathway. Binding of extracellular ligand activates the transmembrane receptor Toll, which requires the novel protein Tube to activate the cytoplasmic serine/threonine kinase Pelle. Pelle activity controls the degradation of the Cactus protein, which is present in a cytoplasmic complex with the Dorsal protein. Once Cactus is degraded in response to signal, Dorsal is free to move into the nucleus where it regulates transcription of specific target genes. The Toll, tube, pelle, cactus, and dorsal genes also appear to be involved in Drosophila immune response. Because the IL-1R-NF-κB pathway plays a role in vertebrate innate immunity and because plant homologues of the Toll-Dorsal pathway are important in plant disease resistance, it is likely that this pathway arose before the divergence of plants and animals as a defense against pathogens.

Myosin is a highly conserved, ubiquitous protein found in all eukaryotic cells, where it provides the motor function for diverse movements such as cytokinesis, phagocytosis, and muscle contraction. All myosins contain an amino-terminal motor/head domain and a carboxy-terminal tail domain. Due to the extensive number of different molecules identified to date, myosins have been divided into seven distinct classes based on the properties of the head domain. One such class, class II myosins, consists of the conventional two-headed myosins that form filaments and are composed of two myosin heavy chain (MYH) subunits and four myosin light chain subunits. The MYH subunit contains the ATPase activity providing energy that is the driving force for contractile processes mentioned above, and numerous MYH isoforms exist in vertebrates to carry out this function. The MYHs involved in striated muscle contraction in mammals are the focus of the current review. The genetics, molecular biology, and biochemical properties of mammalian MYHs are discussed below. MYH gene expression patterns in developing and adult striated muscles are described in detail, as are studies of regulation of MYH genes in the heart. The discovery that mutant MYH isoforms have a causal role in the human disease familial hypertrophic cardiomyopathy (FHC) has implemented structure/function investigations of MYHs. The regulation of MYH genes expressed in skeletal muscle and the potential functional implications that distinct MYH isoforms may have on muscle physiology are addressed.

Proteins that function in transport vesicle docking are being identified at a rapid rate. So-called v- and t-SNAREs form the core of a vesicle docking complex. Additional accessory proteins are required to protect SNAREs from promiscuous binding and to deprotect SNAREs under conditions in which transport vesicle docking should occur. Because access to SNAREs must be regulated, other proteins must also contain specificity determinants to accomplish delivery of transport vesicles to their distinct and specific membrane targets.

Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture. They provide a structural link between the actin cytoskeleton and the extracellular matrix and are regions of signal transduction that relate to growth control. The assembly of focal adhesions is regulated by the GTP-binding protein Rho. Rho stimulates contractility which, in cells that are tightly adherent to the substrate, generates isometric tension. In turn, this leads to the bundling of actin filaments and the aggregation of integrins (extracellular matrix receptors) in the plane of the membrane. The aggregation of integrins activates the focal adhesion kinase and leads to the assembly of a multicomponent signaling complex.

ATP and other nucleotides can be released from cells through regulated pathways, or following the loss of plasma membrane integrity. Once outside the cell, these compounds take on new roles as intercellular signaling molecules that elicit a broad spectrum of physiological responses through the activation of numerous cell surface receptor subtypes. This review summarizes recent advances in the molecular characterization of ATP receptors and discusses roles for cloned receptors in established and novel physiological processes.

Motor proteins perform a wide variety of functions in all eukaryotic cells. Recent advances in the structural and mutagenic analysis of the myosin motor has led to insights into how these motors transduce chemical energy into mechanical work. This review focuses on the analysis of the effects of myosin mutations from a variety of organisms on the in vivo and in vitro properties of this ubiquitous motor and illustrates the positions of these mutations on the high-resolution three-dimensional structure of the myosin motor domain.

Endocytosis in eukaryotic cells is characterized by the continuous and regulated formation of prolific numbers of membrane vesicles at the plasma membrane. These vesicles come in several different varieties, ranging from the actin-dependent formation of phagosomes involved in particle uptake, to smaller clathrin-coated vesicles responsible for the internalization of extracellular fluid and receptor-bound ligands. In general, each of these vesicle types results in the delivery of their contents to lysosomes for degradation. The membrane components of endocytic vesicles, on the other hand, are subject to a series of highly complex and iterative molecular sorting events resulting in their targeting to specific destinations. In recent years, much has been learned about the function of the endocytic pathway and the mechanisms responsible for the molecular sorting of proteins and lipids. This review attempts to integrate these new concepts with long-established views of endocytosis to present a more coherent picture of how the endocytic pathway is organized and how the intracellular transport of internalized membrane components is controlled. Of particular importance are emerging concepts concerning the protein-based signals responsible for molecular sorting and the cytosolic complexes responsible for the decoding of these signals.