Fertilization triggers cytoplasmic movements in the frog egg that lead in mysterious ways to the stabilization of β‐catenin on the dorsal side of the embryo. The novel Huluwa (Hwa) transmembrane protein, identified in China, is translated specifically in the dorsal side, acting as an egg cytoplasmic determinant essential for β‐catenin stabilization. The Wnt signaling pathway requires macropinocytosis and the sequestration inside multivesicular bodies (MVBs, the precursors of endolysosomes) of Axin1 and Glycogen Synthase Kinase 3 (GSK3) that normally destroy β‐catenin. In (...) Xenopus, the Wnt‐like activity of GSK3 inhibitors and of Hwa mRNA can be blocked by brief treatment with inhibitors of membrane trafficking or lysosomes at the 32‐cell stage. In dorsal blastomeres, lysosomal cathepsin is activated and intriguing MVBs surrounded by electron dense vesicles are formed at the 64‐cell stage. We conclude that membrane trafficking and lysosomal activity are critically important for the earliest asymmetries in vertebrate embryonic development. (shrink)

The type II phosphatidylinositol 4-kinases produce the lipid phosphatidylinositol 4-phosphate and participate in a confusing variety of membrane trafficking and signaling roles. This review argues that both historical and contemporary evidence supports the function of the PI4KIIs in numerous trafficking pathways, and that the key to understanding the enzymatic regulation is through membrane interaction and the intrinsic membrane environment. By summarizing new research and examining the trafficking roles of the PI4KIIs in the context of (...) recently solved molecular structures, I highlight how mechanisms of PI4KII function and regulation are providing insights into the development of cancer and in neurological disease. I present an integrated view connecting the cell biology, molecular regulation, and roles in whole animal systems of these increasingly important proteins. The type II phosphatidylinositol 4-kinases are versatile mediators of membrane trafficking, controlling pathways that impact on disease. Recent advances suggest that the membrane lipid environment regulates enzyme activity and that the complexity of trafficking routes can be explained by the ability of these kinases to promote membrane trafficking in different directions. (shrink)

SNAREs (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors) are a large family of proteins that are present on all organelles involved in intracellular vesicle trafficking and secretion. The interaction of complementary SNAREs found on opposing membranes presents an attractive lock‐and‐key mechanism, which may underlie the specificity of vesicle trafficking. Moreover, formation of the tight complex between a vesicle membrane SNARE and corresponding target membrane SNAREs could drive membrane fusion. In synapses, this tight complex, also referred to (...) as the synaptic core complex, is essential for neurotransmitter release. However, recent observations in knockout mice lacking major synaptic SNAREs challenge the prevailing notion on the executive role of these proteins in fusion and open up several questions about their exact role(s) in neurotransmitter release. Persistence of a form of regulated neurotransmitter release in these mutant mice also raises the possibility that other cognate or non‐cognate SNAREs may partially compensate for the loss of a particular SNARE. Future analysis of SNARE function in central synapses will also have implications for the role of these molecules in other vesicle trafficking events such as endocytosis and vesicle replenishment. Such analysis can provide a molecular basis for synaptic processes including certain forms of short‐term synaptic plasticity. BioEssays 24:926–936, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Coronins constitute an evolutionarily conserved family of WD‐repeat actin‐binding proteins, which can be clearly classified into two distinct groups based on their structural features. All coronins possess a conserved basic N‐terminal motif and three to ten WD repeats clustered in one or two core domains. Dictyostelium and mammalian coronins are important regulators of the actin cytoskeleton, while the fly Dpod1 and the yeast coronin proteins crosslink both actin and microtubules. Apart from that, several coronins have been shown to be involved (...) in vesicular transport. C. elegans POD‐1 and Drosophila coro regulate the actin cytoskeleton, but also govern vesicular trafficking as indicated by mutant phenotypes. In both organisms, defects in cytoskeleton and trafficking lead to severe developmental defects ranging from abnormal cell division to aberrant formation of morphogen gradients. Finally, mammalian coronin 7 appears not to execute any cytoskeleton‐related functions, but rather participates in regulating Golgi trafficking. Here, we review recent data providing more insight into molecular mechanisms underlying the regulation of F‐actin structures, cytoskeletal rearrangements and intracellular membrane transport by coronin proteins and the way that they might link cytoskeleton with trafficking in development and disease. BioEssays 27:625–632, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via (...) the cell surface and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins. (shrink)

Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum‐Golgi intermediate compartment (ERGIC). These membranous vesicular‐tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII‐coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI‐dependent transport on to the cis‐Golgi. The mechanisms underlying formation and (...) maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk‐fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC. -/- . (shrink)

Joining an antagonistic phosphoinositide (PtdInsP) kinase and phosphatase into a single protein complex may regulate rapid and local PtdInsP changes. This may be important for processes such as membrane fission that require a specific PtdInsP and that are innately local and rapid. Such a complex could couple vesicle formation, with erasing of the identity of the donor organelle from the vesicle prior to its fusion with target organelles, thus preventing organelle identity intermixing. Coordinating signals are postulated to switch the (...) relative activities of the kinase and phosphatase in a spatio‐temporal manner that matches membrane fission events. The discovery of two such complexes supports this hypothesis. One regulates the interconversion of phosphatidylinositol and PtdIns(3)P by joining the Vps34 PtdIns 3‐kinase and the myotubularin 3‐phosphatases. The other regulates the interconversion between PtdIns(3)P and PtdIns(3,5)P2 through the Fab1/PIKfyve kinase and the Fig4/mFig4 phosphatase. These lipids are essential components of the endosomal identity code. (shrink)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for signalling. We highlight (...) that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions. (shrink)

Phosphatidylinositol 5‐phosphate (PtdIns5P), the least characterized among the three phosphatidylinositol monophosphates, is emerging as a bioactive lipid involved in the control of several cellular functions. Similar to PtdIns3P, it is present in low amounts in mammalian cells, and can be detected at the plasma membrane and endomembranes as well as in the nucleus. Changes in PtdIns5P levels are observed in mammalian cells following specific stimuli or stresses, and in human diseases. Recently, the contribution of several enzymes such as PIKfyve, (...) myotubularins, and type II PtdInsP‐kinases to PtdIns5P metabolism has gained a strong experimental support. Here, we provide a picture emerging from recent studies showing how this lipid can be generated and act as a regulator of membrane and cytoskeleton dynamics, and as a modulator of gene expression. We briefly summarize the current methods and tools for studying PtdIns5P, and discuss how PtdIns5P can integrate and coordinate different functions in a spatiotemporal manner. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety of (...) effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Recently it has become clear that trafficking of integrins to late endosomes is key to the regulation of integrin expression and function during cell migration. Here we discuss the molecular machinery that dictates whether integrins are sorted to recycling endosomes or are targeted to late endosomes and lysosomes. Integrins and other receptors that are sorted to late endosomes are not necessarily degraded and, under certain circumstances, can be spared destruction and returned to the cell surface to drive cell migration (...) and invasion. We will discuss how the exchange of adhesion receptors and other key regulators of cell migration between late endosomes/lysosomes and the plasma membrane can promote dynamic turnover of adhesions during cell migration. (shrink)

Proteins of the exocytotic (secretory) pathway are initially targeted to the endoplasmic reticulum (ER) and then translocated across and/or inserted into the membrane of the ER. During their anterograde transport with the bulk of the membrane flow along the exocytotic pathway, some proteins are selectively retained in various intracellular compartments, while others are sorted to different branches of the pathway. The signals or structural motifs that are involved in these selective targeting processes are being revealed and investigations into (...) the mechanistic nature of these processes are actively underway. (shrink)

Interaction of ligands such as epidermal growth factor and interferon‐γ with the extracellular domains of their plasma membrane receptors results in internalization followed by translocation into the nucleus of the ligand and/or receptor. There has been reluctance, however, to ascribe signaling importance to this, the focus instead being on second messenger pathways, including mobilization of kinases and inducible transcription factors (TFs). The latter, however, fails to explain the fact that so many ligands stimulate the same second messenger cascades/TFs, and (...) yet show distinct gene activation profiles. This is particularly apt in the case of the seven STAT TFs that are held to be the mediators of the distinct cellular functions of over 60 ligands. The current review focuses on five representative nuclear localizing ligands for which there is documentation of translocation into the cytosol and nucleus through well‐characterized pathways, in addition to a role in gene activation by ligand/receptor in the nucleus. BioEssays 26:993‐1004, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The rate‐limiting step in the uptake and metabolism of Dglucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin‐coated pits and vesicles, early (...) endosomes, and tubulo‐vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed. (shrink)

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol‐4‐phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. (...) We believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P‐centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals. (shrink)

The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane‐bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxta‐organellar Ca2+, which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca2+ channel proteins from endolysosomal membranes has provided a unique opportunity to examine the (...) roles of Ca2+ and Ca2+ channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca2+ flux across endolysosomal membranes. In this paper, we discuss the roles of phosphoinositides, Ca2+, and potential interactions between endolysosomal Ca2+ channels and phosphoinositides in endolysosomal dynamics. (shrink)

Phosphoinositides modulate a plethora of functions including signal transduction and membrane trafficking. PtdInsPs are thought to consist of seven interconvertible species that localize to a specific organelle, to which they recruit a set of cognate effector proteins. Here, in reviewing the literature, we argue that this model needs revision. First, PtdInsPs can carry a variety of acyl chains, greatly boosting their molecular diversity. Second, PtdInsPs are more promiscuous in their localization than is usually acknowledged. Third, PtdInsP interconversion is (...) likely achieved through kinase-phosphatase enzyme complexes that coordinate their activities and channel substrates without affecting bulk substrate population. Additionally, we contend that despite hundreds of PtdInsP effectors, our attention is biased toward few proteins. Lastly, we recognize that PtdInsPs can act to nucleate coincidence detection at the effector level, as in PDK1 and Akt. Overall, better integrated models of PtdInsP regulation and function are not only possible but needed. Phosphoinositides are lipids that control many cellular functions. However, the field of PtdInsP signaling is dominated by several dogmatic notions. Here, we offer an updated glimpse on the current state of the field regarding molecular diversity, localization, organization of modifying enzymes, effector types, and effector organization. (shrink)

Recently developed super‐resolution microscopy techniques are changing our understanding of lipid rafts and membrane organisation in general. The lipid raft hypothesis postulates that cholesterol can drive the formation of ordered domains within the plasma membrane of cells, which may serve as platforms for cell signalling and membrane trafficking. There is now a wealth of evidence for these domains. However, their study has hitherto been hampered by the resolution limit of optical microscopy, making the definition of their (...) properties problematic and contentious. New microscopy techniques circumvent the resolution limit and, for the first time, allow the fluorescence imaging of structures on length scales below 200 nm. This review describes such techniques, particularly as applied to the study of membrane organisation, synthesising newly emerging facets of lipid raft biology into a state‐of‐the art model.Editor's suggested further reading in BioEssays: Super‐resolution imaging prompts re‐thinking of cell biology mechanisms Abstract and Quantitative analysis of photoactivated localization microscopy (PALM) datasets using pair‐correlation analysis Abstract. (shrink)

Thirty years after its initial characterization and more than 1000 publications listed in PubMed describing its properties, the small (ca15 kDa) protein profilin continues to surprise us with new, recently discovered functions. Originally described as an actin‐binding protein, profilin has now been shown to interact with more than a dozen proteins in mammalian cells. Some of the more recently described and intriguing interactions are within neurons involving a neuronal profilin family member. Profilin is now regarded as a regulator of various (...) cellular processes such as cytoskeletal dynamics, membrane trafficking and nuclear transport. Profilin is a necessary element in key steps of neuronal differentiation and synaptic plasticity, and embodies properties postulated for a synaptic tag. These findings identify profilin as an important factor linking cellular and behavioural plasticity in neural circuits. BioEssays 30:994–1002, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cytolkinesis ensures proper partitioning of the nucleocytoplasmic contents into two daughter cells. It has generally been thought that cytokinesis is accomplished differently in animals and plants because of the differences in the preparatory phases, into the centrosomal or acentrosomal nature of the process, the presence or absence of rigid cell walls, and on the basis of 'outside-in' or 'inside-out' mechanism. However, this long-standing paradigm needs further reevaluation based on new findings. Recent advances reveal that plant cells, similarly to animal cells, (...) possess astral microtubuies that regulate the cell division plane. Furthermore, endocytosis has been found to be important for cytokinesis in animal and plant cells: vesicles containing endocytosed cargo provide material for the cell plate formation in plants and for closure of the midbody channel in animals. Thus, although the preparatory phases of the cell division process differ between plant and animal cells, the later phases show similarities. We unify these findings in a model that suggests a conserved mode of cytokinesis. (shrink)

Pathogenic bacteria frequently target the endoplasmic reticulum (ER) and mitochondria in order to exploit host functions. ER‐mitochondria inter‐organelle communication is topologically sub‐compartmentalized at mitochondria‐associated ER membranes (MAMs). MAMs are specific membranous microdomains with unique regulatory functions such as lipid synthesis and trafficking, calcium homeostasis, mitochondrial morphology, inflammasome activation, autophagosome formation, and apoptosis. These important cellular processes are all modulated by pathogens to subvert host functions and promote infection, thus it is tempting to assume that pathogenic bacteria target MAMs to (...) subvert these different pathways in their hosts. First lines of evidence that support this hypothesis come from Legionella pneumophila. This intracellular bacterium secretes an effector that exhibits sphingosine‐1 phosphate lyase activity (LpSpl) that seems to target MAMs to modulate the autophagy response to infection. Here we thus propose the concept that MAMs could be targeted by pathogenic bacteria to undermine key host cellular processes. (shrink)

Increased amyloid beta (Aβ) production by sequential cleavage of the amyloid precursor protein (APP) by the β‐ and γ‐secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole system. (...) The Golgi is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Aβ production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment. (shrink)

The emerging field of lipidomics has identified lipids as key players in disease physiology. Their physicochemical diversity allows precise control of cell structure and signaling events through modulation of membrane properties and trafficking of proteins. As such, lipids are important regulators of brain function and have been implicated in neurodegenerative and mood disorders. Importantly, environmental chronic stress has been associated with anxiety and depression and its exposure in rodents has been extensively used as a model to study these (...) diseases. With the accessibility to modern mass‐spectrometry lipidomic platforms, it is now possible to snapshot the extensively interconnected lipid network. Here, we review the fundamentals of lipid biology and outline a framework for the interpretation of lipidomic studies as a new approach to study brain pathophysiology. Thus, lipid profiling provides an exciting avenue for the identification of disease signatures with important implications for diagnosis and treatment of mood disorders. (shrink)

The number of cellular events identified as being directly or indirectly modulated by phosphoinositides dramatically increased in the recent years. Part of the complexity results from the fact that the seven phosphoinositides play second messenger functions in many different areas of growth factors and insulin signaling, cytoskeletal organization, membrane dynamics, trafficking, or nuclear signaling. PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain‐containing inositol 5‐phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5‐position. Here we (...) discuss recent interest in PtdIns(3,4)P2 signaling highlighting its involvement in key cellular mechanisms such as cell adhesion, migration, and cytoskeletal regulation. We question and discuss the involvement of SHIP2 either as a PI 5‐phosphatase or as a scaffold protein in insulin signaling, cytoskeletal dynamics, and endocytosis of growth factor receptors. (shrink)

The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. In (...) reviewing this field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

Cells can change their function by rapidly modulating the levels of certain proteins at the plasma membrane. This rapid modulation is achieved by using a specialised trafficking process called constitutive cycling. The constitutive cycling of a variety of transmembrane proteins such as receptors, channels and transporters has recently been directly demonstrated in a wide range of cell types. This regulation is thought to underlie important biological phenomena such as learning and memory, gastric acid secretion and water and blood (...) glucose homeostasis. This review discusses the molecular mechanisms of constitutive cycling, its regulation by extracellular agents such as hormones and its misregulation in disease states. BioEssays 25:39–46, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

From stem cells to oocyte, Drosophila germ cells undergo a short, defined lineage. Molecular genetic analyses of a collection of female sterile mutations have indicated that a germ cell‐specific organelle called the fusome has a central role at several steps in this lineage. The fusome grows from a prominent spherical organelle to an elongated and branched structure that connects all mitotic sisters in a germ cell syncytium. The organelle is assembled from proteins normally found in the membrane skeleton and, (...) additionally, contains an extensive membranous reticulum, the probable product of differentiation‐dependent vesicle trafficking. This review briefly summarizes a current view of the processes that drive germ cell differentiation, particularly the various roles that the fusome might play in regulating the developmental events. Future efforts will consider to what extent an organelle assembly‐dependent model for differentiation is heuristic and whether the Drosophila fusome represents a homolog of a similar organelle in vertebrate lymphocytes. (shrink)

The polar orientation of cells within a tissue is an intensively studied research area in animal cells. The term planar polarity refers to the common polar arrangement of cells within the plane of an epithelium. In plants, the subcellular analysis of tissue polarity has been limited by the lack of appropriate markers. Recently, research on plant tissue polarity has come of age. Advances are based on studies of Arabidopsis patterning, cell polarity and auxin transport mutants employing the coordinated, polar localization (...) of auxin transporters and the planar polarity of root epidermal hairs as markers. These approaches have revealed auxin transport and response, vesicular trafficking, membrane sterol and cytoskeletal requirements of tissue polarity. This review summarizes recent progress in research on vascular tissue and planar epidermal polarity in the Arabidopsis root and compares it to findings on planar polarity in animals and cell polarity in yeast. BioEssays 26:719–729, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The cellular machinery responsible for conveying proteins between the endoplasmic reticulum and the Golgi is being investigated using genetics and biochemistry. A role for vesicles in mediating protein traffic between the ER and the Golgi has been established by characterizing yeast mutants defective in this process, and by using recently developed cell‐free assays that measure ER to Golgi transport. These tools have also allowed the identification of several proteins crucial to intracellular protein trafficking. The characterization and possible functions of (...) several GTP‐binding proteins, peripheral membrane proteins, and an integral membrane protein during ER to Golgi transport are discussed here. (shrink)

Ubiquitination is essential in mediating diverse cellular functions including protein degradation and trafficking. Ubiquitin‐protein (E3) ligases determine the substrate specificity of the ubiquitination process. The Nedd4 family of E3 ligases is an evolutionarily conserved family of proteins required for the ubiquitination of a large number of cellular targets. As a result, this family regulates a wide variety of cellular processes including transcription, stability and trafficking of plasma membrane proteins, and the degradation of misfolded proteins. The modular architecture (...) of the proteins, comprising a C2 domain, multiple WW domains and a catalytic domain, enables diverse intermolecular interactions and recruitment to various subcellular locations. The WW domains commonly mediate interaction with substrate proteins; however, an increasing number of Nedd4 targets do not contain obvious WW domain‐interaction motifs suggesting the involvement of accessory proteins. This review discusses recent insights into how accessory and adaptor proteins modulate the activities of Nedd4 family members, including recruitment of novel substrates, alteration of subcellular localisation and effects on ubiquitination. BioEssays 28: 617–628, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol‐specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5‐bisphospate and the generation of two second messengers, inositol 1,4,5‐trisphosphate and diacylglycerol. The 3‐phosphoinositide pathway involves protein‐tyrosine kinase‐mediated recruitment and activation of phosphatidylinositol 3‐kinase, resulting (...) in the production of phosphatidylinositol 3,4‐bisphosphate and phosphatidylinositol 3,4,5‐trisphosphate. The 3‐phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3‐phosphoinositide pathway has been implicated in growth factor‐dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3‐kinase has suggested a role for this pathway in vesicular trafficking.In this review the different mechanisms employed by protein‐tyrosine kinases to activate phosphatidylinositol 3‐kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined. (shrink)

Toxoplasma gondii is a highly successful parasite capable of infecting virtually all warm-blooded animals by actively invading nucleated host cells and forming a modified compartment where it replicates within the cytosol. The parasite-containing vacuole provides a safe haven, even in professional phagocytes such as macrophages, which normally destroy foreign microbes. In an effort to eliminate the parasite, the host up-regulates a family of immunity-related p47 GTPases (IRGs), which are recruited to the parasite-containing vacuole, resulting in membrane rupture and digestion (...) of the parasite. To avoid this fate, highly virulent strains of Toxoplasma coat the external surface of their vacuole with a secretory serine/threonine kinase, known as ROP18. At this host-pathogen interface, ROP18 phosphorylates and inactivates IRGs, thereby protecting the parasite from killing. These findings reveal a novel molecular mechanism by which the parasite disarms host innate immunity. (shrink)

Based on an ethnography of French trials for trafficking in human beings and aggravated procuring, this article seeks to contribute to the analysis of the reframing, in penal terms, of the struggles engaged in the name of social justice and women’s rights, of which anti-trafficking policies are particularly emblematic. Studying the judging practices and logics at stake during trials reveals how fantasized representations of the pimp and the victim take on substance. In particular, I argue that judges invoke (...) a set of gendered, sexualized and racialized extra-legal norms, which, along with their legal foundations, constitute their knowledge base and impose a moral and penal hierarchy among litigants. Therefore, not only does this analysis contribute to defining the contours of the elusive figures of the pimp and the victim in the penal arena, it also exposes how maintaining public order is based on the perpetuation of a gendered and sexual national order in the name of gender justice. (shrink)

Organ trafficking in all its various forms is an international crime which could be entirely eliminated if healthcare professionals refused to participate in or be complicit with it. Types of organ trafficking are defined and principal international declarations and resolutions concerning it are discussed. The evidence for the involvement of healthcare professionals is illustrated with examples from South Africa and China. The ways in which healthcare professionals directly or indirectly perpetuate illegal organ transplantation are then considered, including lack (...) of awareness, the paucity of both undergraduate and postgraduate education on organ trafficking, turning a blind eye, advocacy of organ commercialism, and the lure of financial gain. (shrink)

Drug-trafficking in Colombia has been a widely researched phenomenon, especially now, as the country undergoes a transition process with its older guerrilla. Now more than ever it is fundamental to examine how drug-trafficking organizations violent activities affect the consolidation of peace. This article considers different approaches to study violence derived from drug-trafficking, in order to advance towards the objectives of transitional justice. For that matter, this work is based on the idea that drug-trafficking directly generates and (...) reproduces violence which is fueled by the structural violence present in the Colombian context. My thesis is that this phenomenon deters non-repetition guarantees and weakens democracy, which is why there will be three main arguments presented that will revolve around the lack of consensus and the implications of considering drug wars as civil wars, how decisions related to the conceptual apprehension limit the competence of international humanitarian law, and the need for holistic strategies capable of facing drug-trafficking’s political and violent power. Later, alternatives will be explored around the possibilities that each argument offers, as well as which aspects could contribute to a more appropriate approach to combat drug-trafficking. Lastly, I will defend why implementing bottom-up oriented actions can advance towards transitional justice’s intermediate and final objectives, as it is the only alternative that escapes fatalist, utopian or interventionist scenarios. (shrink)

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As (...) the LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon‐like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs. (shrink)

Since the collapse of the Soviet regime, post-communist states have rapidly learned the modern face of slavery. Slavic women have been trafficked to the sex markets of Western Europe, Asia, and North America. The surge in human trafficking is the result of numerous factors, including the dramatic fall of the economic system and complete deterioration of the social safety net. This paper explores the causes and conditions of the growth of the trade in persons in the region, the profile (...) and typical behavior of the victims, and the public perception of the trafficking problem. It identifies the inefficiencies behind the national and international responses to trafficking and the complications for policymaking associated with the stigma attached to sex workers. (shrink)

The aim of this chapter is to draw attention to an overlooked dimension of sex trafficking—namely, its abuse of women’s reproductive rights; to diagnose a tension between international anti-trafficking and refugee law and US anti-trafficking and immigration law; and to show that US anti-trafficking and immigration law is enforcing a misguided conception of victims that denies recognition to agentic victims of human rights abuse. Although women who have been trafficked into sex work should be prime candidates (...) for legal protection, they aren’t. Criminal and legal practices amount to a three-way struggle over women’s bodily integrity and autonomy. Because misconceptions about victimhood perpetuate this cyclical struggle, I argue for legal reforms based on a credible conception of victimhood. (shrink)

Advocacy and scholarship addressing sex trafficking as a human rights issue has become a transnational effort, but there has been less attention to sub-national efficacy. Through analyzing progressive justice system responses to domestic violence in Duluth, Minnesota that have been adopted worldwide, this paper demonstrates how to effectively apply these local advances in order to address sex trafficking on a global scale. This paper makes a theoretical contribution to understanding the intersections between domestic abuse and sex trafficking. (...) A key empirical finding is that a coordinated community response is crucial for advancing domestic abuse training, monitoring, and legislation—and this coordination can also be productively utilized for improving responsiveness to victims of sex trafficking across a diverse range of socio-legal and economic contexts. (shrink)

The Trafficking Victims’ Protection Act of 2000 has been presented as an important tool in combatingthe exploitation and abuse of undocumented workers, especially those forced into prostitution. Through a close reading of the legislation and the debates surrounding its passage, this article argues that the law makes strategic use of anxieties over sexuality, gender, and immigration to further curtail migration. The law does so through the use of misleading statistics creating a moral panic around “sexual slavery,” through the creation (...) of a gendered distinction between “innocent victims” and “guilty migrants,” and through the demand that aid to victims be tied to their willingness to assist in the prosecution of traffickers. As a result, the legislation is less a departure from, than of a piece with, other recent antisex and antiimmigrant policies. (shrink)

Human trafficking is both a human rights violation and the fastest growing criminal industry in the world. This article examines cross-border trafficking of girls and women in Nepal to India. It gives a brief explanation of what is meant by trafficking and then looks at the reasons behind trafficking. In Nepal, women and children are trafficked internally and to India and the Middle East for commercial sexual exploitation or forced marriage, as well as to India and (...) within the country for involuntary servitude as child soldiers, domestic servants, circus entertainment, and factory workers. Nepal and India are both signatories to international conventions and bound by domestic law to combat trafficking, and yet, this scourge continues. There are many laws in place, both in Nepal and India, which regulate the trafficking and prostituting of girls and women. This article looks at how effective these laws and regulations actually are and will look at the reasons for the continuation of trafficking. Despite the formal recognition of girl trafficking as a major problem and the existence of laws to curtail it, trafficking continues. The major problem with Nepal’s and India’s domestic laws is in the lack of enforcement. Finally, this article will look at ways to fight trafficking and make the governments of India and Nepal more effective in their fight against trafficking. (shrink)

While the effect of humanitarian intervention on the recurrence and intensity of armed conflict in a crisis zone has received significant scholarly attention, there has been comparatively less work on the negative externalities of introducing peacekeeping forces into conflict regions. This article demonstrates that large foreign forces create one such externality, namely a previously non-existent demand for human trafficking. Using Kosovo, Haiti, and Sierra Leone as case studies, we suggest that the injection of comparatively wealthy soldiers incentivizes the creation (...) of criminal networks by illicit actors. We theorize further that the magnitude of increase in trafficking should be directly proportional to the size of the foreign force, with larger forces producing larger increases. We find that both hypotheses hold with varying levels of confidence across our three case studies. Despite the benevolent intent of peacekeeping missions, the possibility that they may contribute to human trafficking for the purpose of sexual exploitation runs counter to the spirit of such interventions. This is especially problematic given that trafficking rings, once established, may be adapted to provide weapons and narcotics, thereby planting the seed of further destabilization. (shrink)

One persistent puzzle in the life sciences is the asymmetric lipid composition of the cellular plasma membrane: while the exoplasmic leaflet is enriched in lipids carrying predominantly saturated fatty acids, the cytoplasmic leaflet hosts preferentially lipids with (poly‐)unsaturated fatty acids. Given the high energy requirements necessary for cells to maintain this asymmetry, the question naturally arises regarding its inherent benefits. In this paper, we propose asymmetry to represent a potential solution for harmonizing two conflicting requirements for the plasma (...) class='Hi'>membrane: first, the need to build a barrier for the uncontrolled influx or efflux of substances; and second, the need to form a fluid and dynamic two‐dimensional substrate for signaling processes. We hence view here the plasma membrane as a composite material, where the exoplasmic leaflet is mainly responsible for the functional integrity of the barrier and the cytoplasmic leaflet for fluidity. We reinforce the validity of the proposed mechanism by presenting quantitative data from the literature, along with multiple examples that bolster our model. (shrink)

My aim is to extend and complement the arguments that others have already made for the claim that women who are citizens of economically disadvantaged states and who have been trafficked into sex work in economically advantaged states should be considered candidates for asylum. Familiar arguments cite the sexual violence and forced labor that trafficked women are subjected to along with their well-founded fear of persecution if they’re repatriated. What hasn’t been considered is that reproductive rights are also at stake. (...) I explain how reproductive rights are implicated in sex trafficking. Moreover, I contend that sex traffickers’ abuse of women’s reproductive rights is persecutory and that that this persecutory abuse obliges destination states to offer asylum to transnational sex trafficking victims. I start by sketching reproductive human rights doctrine. I then examine studies of women who are in post-trafficking recovery programs in order to ascertain the impact of their past experience of forced sex work on their reproductive freedom and health. On the basis of these findings, I maintain that, among other outrages, sex trafficking systematically violates victims’ reproductive human rights. In view of this abuse, women trafficked into sex work might seem to be prime candidates for asylum in destination states. Yet, economically well-off destination states are not particularly receptive to this idea, and international law provides some justification for their chilliness. Preliminary to challenging them, I explicate four ways in which international anti-trafficking law and international refugee law interfere with viewing women trafficked into sex work as refugees and approving their applications for asylum. The second half of my paper aims to overcome those legal obstacles. In the interest of parsimony and because there are many continuities between U.S. refugee law and anti-trafficking law and the policies of similar destination states, I focus mainly on the U.S. in this part of the paper. To anchor my argument, I spotlight two precedents in refugee law for taking reproductive human rights seriously and several precedents for treating trafficked women as members of a distinct social group as required by refugee law. I then urge that a law enforcement gestalt has gained undue influence over U.S. legal practices where anti-trafficking law intersects with refugee protection law. A human rights gestalt is needed as a counterweight, for otherwise victims of sex trafficking and the reproductive abuse they’ve suffered are erased. Taking up a human rights perspective and mobilizing the precedents I’ve identified, I show that respecting the reproductive human rights of women who have been trafficked into sex work entails that affluent destination states must recognize their right to asylum. (shrink)

This article focuses on examining the situation of organ trafficking in Africa from the aspect of pragmatist ethics. In the mainstream thought, the broader ethical dilemma of organ trafficking is viewed within the moral contestation of altruism as a rule for organ procurement and the resulting worldwide organ shortage. The incapability of altruistic transplant orthodoxy to serve as an applicable foundation for a public policy is considered as a reason for organ trafficking. In fact, to battle organ (...) trafficking, utilitarian-inclined studies suggest organ selling, compensated donations, and non-directed paid donations as practical alternatives. However, when investigating the context of organ trafficking in Africa, the issue goes beyond the mere moral dilemma of altruism and organ shortage. In the region, organ trafficking is rooted within more systemic, structural, socio-economic, and political problems, grounded in the abuse of transplantation, and connected to transplant tourism and migration, which needs a pragmatic multimodal solutions than the earlier mainstream pathways. In pragmatist ethics, the moral assessment and solutions to the underlying problems depend on the context wherein the moral problem arises. Pragmatist ethics does not stick to absolute moral theories; instead, it focuses on the relevant assessment of the felt moral problem in a given context and aims at seeking solutions afresh. Thus, in the subsequent sections, this article looks at the context of organ trafficking in Africa and reassesses it by incorporating it into the ethical debates of transplantation and organ procurements and trading. The final part of this article reflects on solutions with the reconsideration of the context of transplantation and organ trafficking in the region. (shrink)

It is common to say that the origin of the membrane potential is attributed to transmembrane ion transport, but it is theoretically possible to explain its generation by the mechanism of ion adsorption. It has been previously suggested that the ion adsorption mechanism even leads to potential formulae identical to the famous Nernst equation or the Goldman-Hodgkin-Katz equation. Our further analysis, presented in this paper, indicates that the potential formula based on the ion adsorption mechanism leads to an equation (...) that is a function of the surface charge density of the material and the surface potential of the material. Furthermore, we have confirmed that the equation holds in all the different experimental systems that we have studied. This equation appears to be a key equation that governs the characteristics of the membrane potential in all systems. (shrink)

Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would (...) lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy. (shrink)

Human trafficking is one of the most lucrative international criminal activities and is widespread across a variety of industries. The response to human trafficking in corporate supply chains has been dominated by analyses of due diligence obligations. Existing scholarship, however, has cast doubt on the effectiveness of corporate due diligence in addressing human trafficking, because human trafficking is the outcome of macro-level social structures that are created by and consist of multiple actors, including business. The outsourcing (...) and sub-contracting model provides incentives throughout the global supply chain to sub-contract further to reduce the cost of labor, which has led to human trafficking remaining a pervasive problem. Business responsibility for human trafficking derives from the fact that business decisions and strategies enable the conditions that allow for human trafficking to occur within their supply chains. To address human trafficking, we propose a social connection and political responsibility model, based on Iris Marion Young’s analysis of social connection and structural injustice, that is holistic, forward-looking, and outcomes-oriented. We differentiate between businesses with a strong connection to human trafficking and businesses with a weak connection, and within this distinction delineate different pathways that firms can take to meet their political responsibilities to address human trafficking. We conclude with implications for future research. (shrink)

The passage of the UN Protocol to Prevent, Suppress, and Punish Trafficking in Persons, Especially Women and Children in 2000 marked the first global effort to address human trafficking in 50 years. Since the passage of the UN Protocol international organizations, non-governmental organizations, and individual states have devoted significant resources to eliminating human trafficking. This article critically examines the impact of these efforts with reference to the trends, political, and empirical challenges in data collection and the limitations (...) of international law. I argue that current international law disproportionately addresses the criminal prosecution of traffickers at the expense of trafficking victims’ human rights, and has therefore not yet reached its full potential in the fight against human sex trafficking. (shrink)