Showing papers in "Nature Reviews Molecular Cell Biology in 2001"
TL;DR: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion.
Abstract: When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signalling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that molecular understanding yields clinical benefit: over 25,000 women with breast cancer have now been treated with trastuzumab (Herceptin), a recombinant antibody designed to block the receptor ErbB2. Likewise, small-molecule enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clinical testing. What can this pathway teach us about translating basic science into clinical use?
6,462 citations
TL;DR: Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport.
Abstract: Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport. Rab proteins and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles to their target compartment. These molecules are highly compartmentalized in organelle membranes, making them excellent candidates for determining transport specificity and organelle identity.
3,373 citations
TL;DR: The transcription factor CREB functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory, and how is specificity achieved in these signalling pathways?
Abstract: The transcription factor CREB -- for 'cyclic AMP response element-binding protein' -- functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways?
2,444 citations
TL;DR: New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell–cell adhesion apparatus in molecular terms.
Abstract: Tight junctions are one mode of cell-cell adhesion in epithelial and endothelial cellular sheets. They act as a primary barrier to the diffusion of solutes through the intercellular space, create a boundary between the apical and the basolateral plasma membrane domains, and recruit various cytoskeletal as well as signalling molecules at their cytoplasmic surface. New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell-cell adhesion apparatus in molecular terms.
2,366 citations
TL;DR: This review describes integrin functions, mechanosensors, molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces.
Abstract: Integrin-mediated cell adhesions provide dynamic, bidirectional links between the extracellular matrix and the cytoskeleton Besides having central roles in cell migration and morphogenesis, focal adhesions and related structures convey information across the cell membrane, to regulate extracellular-matrix assembly, cell proliferation, differentiation, and death This review describes integrin functions, mechanosensors, molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces
2,053 citations
TL;DR: A single family of proteases, the caspases, has long been considered the pivotal executioner of all programmed cell death, but recent findings of evolutionarily conserved, caspase-independent controlled death mechanisms have opened new perspectives on the biology of cell demise.
Abstract: A single family of proteases, the caspases, has long been considered the pivotal executioner of all programmed cell death However, recent findings of evolutionarily conserved, caspase-independent controlled death mechanisms have opened new perspectives on the biology of cell demise, with particular implications for neurobiology, cancer research and immunological processes
1,690 citations
TL;DR: An overview of the many mitotic kinases that regulate cell division and the fidelity of chromosome transmission is given.
Abstract: Mitosis and cytokinesis are undoubtedly the most spectacular parts of the cell cycle. Errors in the choreography of these processes can lead to aneuploidy or genetic instability, fostering cell death or disease. Here, I give an overview of the many mitotic kinases that regulate cell division and the fidelity of chromosome transmission.
1,540 citations
TL;DR: Glycogen synthase kinase 3 was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions.
Abstract: Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.
1,485 citations
TL;DR: It is shown that the conjugation of proteins with a small protein called ubiquitin touches upon all aspects of eukaryotic biology, and its defective regulation is manifest in diseases that range from developmental abnormalities and autoimmunity to neurodegenerative diseases and cancer.
Abstract: Ubiquitylation ? the conjugation of proteins with a small protein called ubiquitin ? touches upon all aspects of eukaryotic biology, and its defective regulation is manifest in diseases that range from developmental abnormalities and autoimmunity to neurodegenerative diseases and cancer. A few years ago, we could only have dreamt of the complex arsenal of enzymes dedicated to ubiquitylation. Why has nature come up with so many ways of doing what seems to be such a simple job?
1,403 citations
TL;DR: Multi-ubiquitin chains at least four subunits long are required for efficient recognition and degradation of ubiquitylated proteins by the proteasome, but other functions of ubiquitin have been discovered that do not involve the protease.
Abstract: Multi-ubiquitin chains at least four subunits long are required for efficient recognition and degradation of ubiquitylated proteins by the proteasome, but other functions of ubiquitin have been discovered that do not involve the proteasome. Some proteins are modified by a single ubiquitin or short ubiquitin chains. Instead of sending proteins to their death through the proteasome, monoubiquitylation regulates processes that range from membrane transport to transcriptional regulation.
1,242 citations
TL;DR: Live cell imaging, in combination with photobleaching, energy transfer or fluorescence correlation spectroscopy are providing unprecedented insights into the movement of proteins and their interactions with cellular components.
Abstract: Since the advent of the green fluorescent protein, the subcellular localization, mobility, transport routes and binding interactions of proteins can be studied in living cells. Live cell imaging, in combination with photobleaching, energy transfer or fluorescence correlation spectroscopy are providing unprecedented insights into the movement of proteins and their interactions with cellular components. Remarkably, these powerful techniques are accessible to non-specialists using commercially available microscope systems.
TL;DR: Functional studies have provided exciting insights into how SNARE proteins interact with each other to generate the driving force needed to fuse lipid bilayers.
Abstract: SNARE proteins have been proposed to mediate all intracellular membrane fusion events. There are over 30 SNARE family members in mammalian cells and each is found in a distinct subcellular compartment. It is likely that SNAREs encode aspects of membrane transport specificity but the mechanism by which this specificity is achieved remains controversial. Functional studies have provided exciting insights into how SNARE proteins interact with each other to generate the driving force needed to fuse lipid bilayers.
TL;DR: In this article, the genes required for autophagy in yeast have been analyzed and two ubiquitin-like systems were found to be involved in the membrane dynamics of the process.
Abstract: Recent analyses of the genes required for autophagy ? intracellular bulk protein degradation ? in yeast have revealed two ubiquitin-like systems, both of which are involved in the membrane dynamics of the process. Molecular dissection of these systems is now revealing some surprises.
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TL;DR: Since it was identified a decade ago, cyclin-dependent kinase 5 has emerged as a crucial regulator of neuronal migration in the developing central nervous system.
Abstract: Since it was identified a decade ago, cyclin-dependent kinase 5 (CDK5) has emerged as a crucial regulator of neuronal migration in the developing central nervous system. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes - from adhesion and motility, to synaptic plasticity and drug addiction. Recent evidence indicates that deregulation of this kinase is involved in the pathology of neurodegenerative diseases.
TL;DR: It is suggested that opening of a multiprotein complex called the mitochondrial permeability transition pore complex is sufficient (and, usually, necessary) for triggering apoptosis.
Abstract: There is widespread agreement that mitochondria have a function in apoptosis, but the mechanisms behind their involvement remain controversial Here we suggest that opening of a multiprotein complex called the mitochondrial permeability transition pore complex is sufficient (and, usually, necessary) for triggering apoptosis
TL;DR: ETS-domain transcription-factor networks represent a model for how combinatorial gene expression is achieved and a complex series of inter and intramolecular interactions, and signalling pathways impinge on these proteins to further regulate their action.
Abstract: ETS-domain transcription-factor networks represent a model for how combinatorial gene expression is achieved. These transcription factors interact with a multitude of co-regulatory partners to elicit gene-specific responses and drive distinct biological processes. These proteins are controlled by a complex series of inter and intramolecular interactions, and signalling pathways impinge on these proteins to further regulate their action.
TL;DR: The history, structure and function ofamins are described, which are large actin-binding proteins that stabilize delicate three-dimensional actin webs and link them to cellular membranes.
Abstract: Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin webs and link them to cellular membranes. They integrate cellular architectural and signalling functions and are essential for fetal development and cell locomotion. Here, we describe the history, structure and function of this group of proteins.
TL;DR: Pro- and anti-apoptotic members of the Bcl-2 family control the permeability of the outer mitochondrial membrane by forming autonomous pores in the membrane or by collaborating with components of the permeable transition pore.
Abstract: Pro- and anti-apoptotic members of the Bcl-2 family control the permeability of the outer mitochondrial membrane. They could do this either by forming autonomous pores in the membrane or by collaborating with components of the permeability transition pore. Here we discuss why we favour the first of these possibilities.
TL;DR: A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance.
Abstract: The retinoblastoma protein (RB) and p53 transcription factor are regulated by two distinct proteins that are encoded by the INK4a/ARF locus. Genes encoding these four tumour suppressors are disabled, either in whole or in part, in most human cancers. A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance.
TL;DR: The mechanisms by which rotation and catalysis are coupled in the working enzyme are now being unravelled on a molecular scale.
Abstract: ATP synthase can be thought of as a complex of two motors--the ATP-driven F1 motor and the proton-driven Fo motor--that rotate in opposite directions. The mechanisms by which rotation and catalysis are coupled in the working enzyme are now being unravelled on a molecular scale.
TL;DR: The levels of cellular messenger RNA transcripts can be regulated by controlling the rate at which the mRNA decays, but what are the sequence elements and factors that control the half-lives of mRNAs?
Abstract: The levels of cellular messenger RNA transcripts can be regulated by controlling the rate at which the mRNA decays. Because decay rates affect the expression of specific genes, they provide a cell with flexibility in effecting rapid change. Moreover, many clinically relevant mRNAs — including several encoding cytokines, growth factors and proto-oncogenes — are regulated by differential RNA stability. But what are the sequence elements and factors that control the half-lives of mRNAs?
TL;DR: Mycobacterium tuberculosis is a highly successful pathogen that parasitizes the macrophages of its host and the interplay between the pathogen and its host cell reflects a constant battle for control.
Abstract: Mycobacterium tuberculosis is a highly successful pathogen that parasitizes the macrophages of its host. Its success can be attributed directly to its ability to manipulate the phagosome that it resides in and to prevent the normal maturation of this organelle into an acidic, hydrolytic compartment. As the macrophage is key to clearing the infection, the interplay between the pathogen and its host cell reflects a constant battle for control.
TL;DR: Organelles in the endocytic pathway are composed of a mosaic of structural and functional regions, indicating that membrane organization might be modular.
Abstract: Organelles in the endocytic pathway are composed of a mosaic of structural and functional regions. These regions consist, at least in part, of specialized protein-lipid domains within the plane of the membrane, or of protein complexes associated with specific membrane lipids. Whereas some of these molecular assemblies can be found in more than one compartment, a given combination seems to be unique to each compartment, indicating that membrane organization might be modular.
TL;DR: Covalent modification of cellular proteins by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport, signal transduction, stress response and cell-cycle progression, but, in contrast to ubiquitylation, sumoylation seems to enhance their stability or modulate their subcellular compartmentalization.
Abstract: Covalent modification of cellular proteins by the ubiquitin-like modifier SUMO regulates various cellular processes, such as nuclear transport, signal transduction, stress response and cell-cycle progression. But, in contrast to ubiquitylation, sumoylation does not tag proteins for degradation, but seems to enhance their stability or modulate their subcellular compartmentalization.
TL;DR: Responses to extracellular stimuli are often transduced from cell-surface receptors to protein tyrosine kinases which, when activated, initiate the formation of protein complexes that transmit signals throughout the cell.
Abstract: Responses to extracellular stimuli are often transduced from cell-surface receptors to protein tyrosine kinases which, when activated, initiate the formation of protein complexes that transmit signals throughout the cell. A prominent component of these complexes is the product of the proto-oncogene c-Cbl, which specifically targets activated protein tyrosine kinases and regulates their signalling. How, then, does this multidomain protein shape the responses generated by these signalling complexes?
TL;DR: The physiological relevance of some of the proposed mechanisms by which PKB/AKT mediates many of its effects has been questioned, and recent work using new reagents and approaches has revealed some cracks in understanding of this important molecule.
Abstract: Since its discovery 10 years ago, the potential functions of protein kinase B (PKB)/AKT have been catalogued with increasing efficiency. The physiological relevance of some of the proposed mechanisms by which PKB/AKT mediates many of its effects has been questioned, and recent work using new reagents and approaches has revealed some cracks in our understanding of this important molecule, and also hinted that these effects may involve other players.
TL;DR: Ras-like GTPases are ubiquitously expressed, evolutionarily conserved molecular switches that couple extracellular signals to various cellular responses, ranging from modulation of growth and differentiation to secretion, integrin-mediated cell adhesion and morphogenesis.
Abstract: Ras-like GTPases are ubiquitously expressed, evolutionarily conserved molecular switches that couple extracellular signals to various cellular responses. Rap1, the closest relative of Ras, has attracted much attention because of the possibility that it regulates Ras-mediated signalling. Rap1 is activated by extracellular signals through several regulatory proteins, and it might function in diverse processes, ranging from modulation of growth and differentiation to secretion, integrin-mediated cell adhesion and morphogenesis.
TL;DR: The regulated translation of messenger RNA is essential for cell-cycle progression, establishment of the body plan during early development, and modulation of key activities in the central nervous system.
Abstract: The regulated translation of messenger RNA is essential for cell-cycle progression, establishment of the body plan during early development, and modulation of key activities in the central nervous system. Cytoplasmic polyadenylation, which is one mechanism of controlling translation, is driven by CPEB — a highly conserved, sequence-specific RNA-binding protein that binds to the cytoplasmic polyadenylation element, and modulates translational repression and mRNA localization. What are the features and functions of this multifaceted protein?
TL;DR: Old and new data point to a new vista of inositol phosphates, with functions in many diverse aspects of cell biology, such as ion-channel physiology, membrane dynamics and nuclear signalling.
Abstract: Following the discovery of inositol-1,4,5-trisphosphate as a second messenger, many other inositol phosphates were discovered in quick succession, with some understanding of their synthesis pathways and a few guesses at their possible functions. But then it all seemed to go comparatively quiet, with an explosion of interest in the inositol lipids. Now the water-soluble phase is once again becoming a focus of interest. Old and new data point to a new vista of inositol phosphates, with functions in many diverse aspects of cell biology, such as ion-channel physiology, membrane dynamics and nuclear signalling.
TL;DR: A new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems to understand this dance of complex assemblies of interacting proteins.
Abstract: Complex assemblies of interacting proteins carry out most of the interesting jobs in a cell, such as metabolism, DNA synthesis, movement and information processing. These physiological properties play out as a subtle molecular dance, choreographed by underlying regulatory networks. To understand this dance, a new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems.