Showing papers in "Cell Adhesion & Migration in 2010"
TL;DR: Recent investigations into the effect of mean pore size in collagen-glycosaminoglycan scaffolds with pore sizes ranging from 85–325 μm are discussed and how it has provided an insight into the divergence within the literature.
Abstract: Mean pore size is an essential aspect of scaffolds for tissue-engineering. If pores are too small cells cannot migrate in towards the center of the construct limiting the diffusion of nutrients and removal of waste products. Conversely, if pores are too large there is a decrease in specific surface area available limiting cell attachment. However the relationship between scaffold pore size and cell activity is poorly understood and as a result there are conflicting reports within the literature on the optimal pore size required for successful tissue-engineering. Previous studies in bone tissue-engineering have indicated a range of mean pore sizes (96–150 µm) to facilitate optimal attachment. Other studies have shown a need for large pores (300–800 µm) for successful bone growth in scaffolds. These conflicting results indicate that a balance must be established between obtaining optimal cell attachment and facilitating bone growth. In this commentary we discuss our recent investigations into the effect of mean pore size in collagen-glycosaminoglycan (CG) scaffolds with pore sizes ranging from 85–325 μm and how it has provided an insight into the divergence within the literature.
455 citations
TL;DR: Understanding the regulation and functional roles of Snail will shed new light on the mechanism of tumor progression and the development of novel cancer therapies.
Abstract: Snail has moved into the fast lane of development and cancer biology with the epithelial-mesenchymal transition (EMT) emerging as one of the hottest topics in medical science within the past few years. Snail not only acts primarily as a key inducer of EMT but also plays an important role in cell survival, immune regulation and stem cell biology. This review focuses on the regulation of Snail and discusses the EMT-dependent and -independent functions of Snail in development and disease. Understanding the regulation and functional roles of Snail will shed new light on the mechanism of tumor progression and the development of novel cancer therapies.
213 citations
TL;DR: Cell signaling, extracellular matrix and cell-cell contacts are all critical for the initial migration, pauses, continued migration, and condensation of cardiac neural crest cells.
Abstract: Cardiac neural crest cells originate as part of the postotic caudal rhombencephalic neural crest stream. Ectomesenchymal cells in this stream migrate to the circumpharyngeal ridge and then into the caudal pharyngeal arches where they condense to form first a sheath and then the smooth muscle tunics of the persisting pharyngeal arch arteries. A subset of the cells continue migrating into the cardiac outflow tract where they will condense to form the aorticopulmonary septum. Cell signaling, extracellular matrix and cell-cell contacts are all critical for the initial migration, pauses, continued migration, and condensation of these cells. This review elucidates what is currently known about these factors.
119 citations
TL;DR: The transmembrane (TM) domains of receptor tyrosine kinases (RTKs) play an active role in signaling, and recent studies of RTK TM domain dimerization energetics, possible synergies between domains, and the effects of pathogenic RTKTM mutations on structure andDimerization are discussed.
Abstract: The transmembrane (TM) domains of receptor tyrosine kinases (RTKs) play an active role in signaling. They contribute to the stability of full-length receptor dimers and to maintaining a signaling-competent dimeric receptor conformation. In an exciting new development, two structures of RTK TM domains have been solved, a break-through achievement in the field. Here we review these structures, and we discuss recent studies of RTK TM domain dimerization energetics, possible synergies between domains, and the effects of pathogenic RTK TM mutations on structure and dimerization.
102 citations
TL;DR: How the developmental functions of the neuropilins are influenced by the cellular and even subcellular context the neuro pilins find themselves in is reviewed.
Abstract: Neuropilins are highly conserved single pass transmembrane proteins specific to vertebrates. They were originally identified as adhesion molecules in the nervous system, but were subsequently rediscovered as the ligand binding subunit of the class 3 semaphorin receptor in neurons and then as blood vessel receptors for the vascular endothelial growth factor VEGF. More recently they have also been implicated as mediators of the T-cell immune response and as key prognostic markers in several types of cancer. Because neuropilins bind multiple ligands and associate with several different types of co-receptors, they variably promote cell adhesion, repulsion or attraction. Which response they ultimately invoke is decided by the cellular and even subcellular context the neuropilins find themselves in. Here, we review how the developmental functions of the neuropilins are influenced by such different contexts.
79 citations
TL;DR: This review attempts to give an overview of current knowledge about these interactions, from structural data to therapeutic perspectives, focusing on bitopic proteins involved in cell signaling.
Abstract: As a whole, integral membrane proteins represent about one third of sequenced genomes, and more than 50% of currently available drugs target membrane proteins, often cell surface receptors. Some membrane protein classes, with a defined number of transmembrane (TM) helices, are receiving much attention because of their great functional and pharmacological importance, such as G protein-coupled receptors possessing 7 TM segments. Although they represent roughly half of all membrane proteins, bitopic proteins (with only 1 TM helix) have so far been less well characterized. Though they include many essential families of receptors, such as adhesion molecules and receptor tyrosine kinases, many of which are excellent targets for biopharmaceuticals (peptides, antibodies, et al.). A growing body of evidence suggests a major role for interactions between TM domains of these receptors in signaling, through homo and heteromeric associations, conformational changes, assembly of signaling platforms, etc. Significantly,...
78 citations
TL;DR: The goal of this review is to summarize the knowledge about the dysregulation of major cell-cycle regulators in lung cancer pathogenesis, and to discuss the use of these proteins as targets for therapeutic intervention.
Abstract: Cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size, and DNA integrity. Progression throughout the cell cycle is based on the activation of different CDK-cyclin complexes that prevent cells from entering into a new phase until thay have successfully complete the previous one. In addition, a series of cell cycle checkpoints are designed to preserve genome integrity and chromosomal stability. Neoplastic lung cells develop the ability to bypass several of these checkpoints, and tumor cell proliferation is frequently associated with genetic or epigenetic alterations in key regulators of the cell cycle. The goal of this review is to summarize the knowledge about the dysregulation of major cell-cycle regulators in lung cancer pathogenesis, and to discuss the use of these proteins as targets for therapeutic intervention.
77 citations
TL;DR: It is shown that the vagal-level neural crest cells exhibit modest developmental bias, and there are differences in the migratory behavior between the anterior and the posterior vagal Neural crest cells reminiscent of the cranial and the trunk neural crest, respectively.
Abstract: Neural crest cells are pluripotent cells that emerge from the neural epithelium, migrate extensively, and differentiate into numerous derivatives, including neurons, glial cells, pigment cells and connective tissue. Major questions concerning their morphogenesis include: 1) what establishes the pathways of migration and 2) what controls the final destination and differentiation of various neural crest subpopulations. These questions will be addressed in this review. Neural crest cells from the trunk level have been explored most extensively. Studies show that melanoblasts are specified shortly after they depart from the neural tube, and this specification directs their migration into the dorsolateral pathway. We also consider other reports that present strong evidence for ventrally migrating neural crest cells being similarly fate restricted. Cranial neural crest cells have been less analyzed in this regard but the preponderance of evidence indicates that either the cranial neural crest cells are not fate-restricted, or are extremely plastic in their developmental capability and that specification does not control pathfinding. Thus, the guidance mechanisms that control cranial neural crest migration and their behavior vary significantly from the trunk. The vagal neural crest arises at the axial level between the cranial and trunk neural crest and represents a transitional cell population between the head and trunk neural crest. We summarize new data to support this claim. In particular, we show that: 1) the vagal-level neural crest cells exhibit modest developmental bias; 2) there are differences in the migratory behavior between the anterior and the posterior vagal neural crest cells reminiscent of the cranial and the trunk neural crest, respectively; 3) the vagal neural crest cells take the dorsolateral pathway to the pharyngeal arches and the heart, but the ventral pathway to the peripheral nervous system and the gut. However, these pathways are not rigidly specified because of prior fate restriction. Understanding the molecular, cellular and behavioral differences between these three populations of neural crest cells will be of enormous assistance when trying to understand the evolution of the neck.
71 citations
TL;DR: The crucial components of the thymus microenvironment and their complex interactions during the T-cell maturation process with the objective of contributing to a better understanding of the function of theThymus as well as assist in the search for new therapeutic approaches to improve the immune response in various pathological conditions are summarized here.
Abstract: The thymus plays a crucial role in the development of T lymphocytes by providing an inductive microenvironment in which committed progenitors undergo proliferation, T-cell receptor gene rearrangements and thymocyte differentiate into mature T cells. The thymus microenvironment forms a complex network of interaction that comprises non lymphoid cells (e.g., thymic epithelial cells, TEC), cytokines, chemokines, extracellular matrix elements (ECM), matrix metalloproteinases and other soluble proteins. The thymic epithelial meshwork is the major component of the thymic microenvironment, both morphologically and phenotypically limiting heterogeneous regions in thymic lobules and fulfilling an important role during specific stages of T-cell maturation. The process starts when bone marrow-derived lymphocyte precursors arrive at the outer cortical region of the thymic gland and begin to mature into functional T lymphocytes that will finally exit the thymus and populate the peripheral lymphoid organs. During their journey inside the thymus, thymocytes must interact with stromal cells (and their soluble products) and extracellular matrix proteins to receive appropriate signals for survival, proliferation and differentiation. The crucial components of the thymus microenvironment, and their complex interactions during the T-cell maturation process are summarized here with the objective of contributing to a better understanding of the function of the thymus, as well as assisting in the search for new therapeutic approaches to improve the immune response in various pathological conditions.
69 citations
TL;DR: This review focuses on the function of the ErbB family of receptor tyrosine kinases with a special emphasis on the role of the transmembrane domain and on the mechanisms underlying regulated and deregulated signaling.
Abstract: Among the many transmembrane receptor classes, the receptor tyrosine kinases represent an important superfamily, involved in many cellular processes like embryogenesis, development and cell division. Deregulation and dysfunctions of these receptors can lead to various forms of cancer and other diseases. Mostly, only fragmented knowledge exists about functioning of the whole receptors, and many studies have been performed on isolated receptor domains. In this review we focus on the function of the ErbB family of receptor tyrosine kinases with a special emphasis on the role of the transmembrane domain and on the mechanisms underlying regulated and deregulated signaling. Many general aspects of ErbB receptor structure and function have been analyzed and described. All human ErbBs appear to form homo- and heterodimers within cellular membranes and the single transmembrane domain of the receptors is involved in dimerization. Additionally, only defined structures of the transmembrane helix dimer allows signalin...
66 citations
TL;DR: Theses E3 ubiquitin ligases regulate cell adhesion and (or) migration through ubiquitination of their specific substrates.
Abstract: Recent studies have demonstrated that a number of E3 ubiquitin ligases, including Cbl, Smurf1, Smurf2, HDM2, BCA2, SCF(beta-TRCP) and XRNF185, play important roles in cell adhesion and migration. Cbl negatively regulates cell adhesion via alpha integrin and Rap1 and inhibits actin polymerization by ubiquitinating mDab1 and WAVE2. Smurf1 regulates cell migration through ubiquitination of RhoA, talin head domain and hPEM2, while Smurf2 ubiquitinates Smurf1, TGFbeta type I receptor and RaplB to modulate cell migration and adhesion. HDM2 negatively regulates cell migration by targeting NFAT (a transcription factor) for ubiquitination and degradation, while SCF(beta-TRCP) ubiquitinates Snail (a transcriptional repressor of E-cadherin) to inhibit cell migration. TRIM32 promotes cell migration through ubiquitination of Abl interactor 2 (Abi2), a tumor suppressor. RNF5 and XRNF185 modulate cell migration by ubiquitinating paxillin. Thus, these E3 ubiquitin ligases regulate cell adhesion and (or) migration through ubiquitination of their specific substrates.
TL;DR: It is hoped that blocking MET signaling may one day become an effective treatment for some lung cancers.
Abstract: The MET tyrosine kinase signaling pathway is upregulated in many cancers, including lung cancer. The pathway normally promotes mitosis, cell motility and cell survival; but in cancer it can also promote cell proliferation, invasion, metastasis, and angiogenesis. The activating ligand, hepatocyte growth factor, is normally secreted by fibroblasts and smooth muscle cells, but can also be produced by tumor cells. MET upregulation in lung cancer is caused by overexpression and mutation. These mutations can vary with ethnicity. MET signaling affects cytoskeletal proteins such as paxillin, which participates in cell adhesion, growth and motility. Therapeutic approaches that block MET signaling are being studied, and include the use of: small interference RNA, Geldanamycin, competitive HGF homologues, decoy receptors, and direct MET inhibitors such as K252a, SU11274, PHA665752 and PF2341066. It is hoped that blocking MET signaling may one day become an effective treatment for some lung cancers.
TL;DR: It is suggested that ephrin-A3 acts as a repulsive cue that restricts cortical interneurons from entering inappropriate regions and thus contributes to define the migratory route of cortical Interneuron migration.
Abstract: Cortical interneurons are born in the proliferative zones of the ganglionic eminences in the subpallium and migrate to the developing cortex along well-defined tangential routes. The mechanisms regulating interneuron migration are not completely understood. Here we examine the role of class-A members of the Eph/ephrin system in directing the migration of interneurons. In situ hybridizations demonstrated that ephrin A3 is expressed in the developing striatum, an area that is strictly avoided by migrating cortical interneurons in vivo, which express the EphA4 receptor. We then examined interneuron migration in grafting experiments, where explants of the medial ganglionic eminence (MGE) from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wild-type littermate embryos. After blocking ephrin-A ligands, many interneurons invaded the striatal anlage. Moreover, stripe assay experiments revealed that ephrin-A3 acts as a repellent cue for neurons from t...
TL;DR: The rising evidences about the role that integrins can play in the physiopathology of non small cell lung carcinomas by regulating cell adhesion as well as the activation of growth factors and the traffic of their cognate receptors are examined.
Abstract: The poor prognosis of most non small cell lung carcinomas is due to their ability to efficiently invade surrounding tissues and blood vessels, finally metastasizing to distant organs. Integrin mediated adhesive interaction with the surrounding extracellular matrix is a key limiting step in the regulation of the invasive properties of several cancer cell types. Here, we examine the rising evidences about the role that integrins can play in the physiopathology of non small cell lung carcinomas by regulating cell adhesion as well as the activation of growth factors and the traffic of their cognate receptors. Modulation of the signaling pathways controlled by integrins in lung cancer cells might offer the opportunity to design and develop new drugs that might be successfully combined with conventional chemotherapy and radiotherapy.
TL;DR: Investigation of the role of canonical Wnt signaling in the expression of cadherin-7 and cadhersin-11 by treating neural crest cells with Wnt3a ligand shows that cadherIn-7and cadher in-11 expressed by the migrating Neural crest cells can be regulated by the canonical WNT pathway.
Abstract: In neural crest cell development, the expression of the cell adhesion proteins cadherin-7 and cadherin-11 commences after delamination of the neural crest cells from the neuroepithelium. The canonical Wnt signaling pathway is known to drive this delamination step and is a candidate for inducing expression of these cadherins at this time. This project was initiated to investigate the role of canonical Wnt signaling in the expression of cadherin-7 and cadherin-11 by treating neural crest cells with Wnt3a ligand. Expression of cadherin-11 was first confirmed in the neural crest cells for the chicken embryo. The changes in the expression level of cadherin-7 and -11 following the treatment with Wnt3a ligand were studied using real-time RT-PCR and immunostaining. Statistically significant up-regulation in the mRNA expression of cadherin-7 and cadherin-11 and in the amount of cadherin-7 and cadherin-11 protein found in cell-cell interfaces between neural crest cells was observed in response to Wnt, demonstrating...
TL;DR: Transitions between epithelial and mesenchymal states drive key morphogenetic events in the early vertebrate embryo, including gastrulation, germ layer formation and somitogenesis.
Abstract: Multicellular organisms arise from the generation of different cell types and the organization of cells into tissues and organs. Cells of metazoa display two main phenotypes, the ancestral epithelial state and the recent mesenchymal derivative. Epithelial cells are usually stationary and reside in two-dimensional sheets. By contrast mesenchymal cells are loosely packed and can move to new positions, thereby providing a vehicle for cell rearrangement, dispersal and novel cell-cell interactions. Transitions between epithelial and mesenchymal states drive key morphogenetic events in the early vertebrate embryo, including gastrulation, germ layer formation and somitogenesis. The cell behaviors and molecular mechanisms promoting transitions between these two states in the early mouse embryo are discussed in this review.
TL;DR: The goal is to combine the understanding of cell adhesion to the extracellular matrix with the regulation of cell-cell adhesion and the involvement of the planar cell polarity signaling-pathway in guiding the migration of cranial neural crest cells during embryogenesis.
Abstract: This review focuses on recent advances in the field of cranial neural crest cell migration in Xenopus laevis with specific emphasis on cell adhesion and the regulation of cell migration. Our goal is to combine the understanding of cell adhesion to the extracellular matrix with the regulation of cell-cell adhesion and the involvement of the planar cell polarity signaling-pathway in guiding the migration of cranial neural crest cells during embryogenesis.
TL;DR: The current knowledge of PDGF function during neural crest cell (NCC) development is examined, focusing on its role in the formation of different neural crest-derived tissues and the implications for PDGF receptors in NCC-related human birth defects.
Abstract: Activation of platelet derived growth factor (PDGF) receptors causes context-dependent cellular responses, including proliferation and migration, and studies in model organisms have demonstrated that this receptor family (PDGFRα and PDGFRβ) is required in many mesenchymal and migratory cell populations during embryonic development. One of these migratory cell populations is the neural crest, which forms cranial bone and mesenchyme, sympathetic neurons and ganglia, melanocytes, and smooth muscle. Mice with disruption of PDGF signaling exhibit defects in some of these neural crest derivatives including the palate, aortic arch, salivary gland, and thymus. Although many of these neural crest defects were identified many years ago, the mechanism of action of PDGF in neural crest remains controversial. In this review, we examine the current knowledge of PDGF function during neural crest cell (NCC) development, focusing on its role in the formation of different neural crest-derived tissues and the implications for PDGF receptors in NCC-related human birth defects.
TL;DR: This review highlights studies that have used live imaging to provide novel insight into NCC migration and discusses how continued use of such techniques can advance the understanding of NCC biology.
Abstract: Neural crest cells (NCCs) are a remarkable, dynamic group of cells that travel long distances in the embryo to reach their target sites. They are responsible for the formation of craniofacial bones and cartilage, neurons and glia in the peripheral nervous system, and pigment cells. Live imaging of NCCs as they traverse the embryo has been critical to increasing our knowledge of their biology. NCCs exhibit multiple behaviors and communicate with each other and their environment along each step of their journey. Imaging combined with molecular manipulations has led to insights into the mechanisms controlling these behaviors. In this review, we highlight studies that have used live imaging to provide novel insight into NCC migration and discuss how continued use of such techniques can advance our understanding of NCC biology.
TL;DR: It is proposed that the time course and extent of EMT do not depend merely on the identity of the EMT transcriptional regulators and their cellular effectors but rather on the combination of molecular players recruited and on the possible coordination of E MT with other cellular processes.
Abstract: Although epithelial to mesenchymal transitions (EMT) are often viewed as a unique event, they are characterized by a great diversity of cellular processes resulting in strikingly different outcomes. They may be complete or partial, massive or progressive, and lead to the complete disruption of the epithelium or leave it intact. Although the molecular and cellular mechanisms of EMT are being elucidated owing chiefly from studies on transformed epithelial cell lines cultured in vitro or from cancer cells, the basis of the diversity of EMT processes remains poorly understood. Clues can be collected from EMT occuring during embryonic development and which affect equally tissues of ectodermal, endodermal or mesodermal origins. Here, based on our current knowledge of the diversity of processes underlying EMT of neural crest cells in the vertebrate embryo, we propose that the time course and extent of EMT do not depend merely on the identity of the EMT transcriptional regulators and their cellular effectors but rather on the combination of molecular players recruited and on the possible coordination of EMT with other cellular processes.
TL;DR: Five guidance molecule families and their corresponding receptors are described, including the semaphorins/neuropilins/plexins, ephrins and Eph receptors, netrin/DCC/UNC5, Slit/Robo and Notch/Delta.
Abstract: Guidance molecules were first described in the nervous system to control axon outgrowth direction. They are also widely expressed outside the nervous system where they control cell migration, tissue development and establishment of the vascular network. In addition, they are involved in cancer development, tumor angiogenesis and metastasis. This review is primarily focused on their functions in lung cancer and their involvement in lung development is also presented. Five guidance molecule families and their corresponding receptors are described, including the semaphorins/neuropilins/plexins, ephrins and Eph receptors, netrin/DCC/UNC5, Slit/Robo and Notch/Delta. In addition, the possibility to target these molecules as a therapeutic approach in cancer is discussed.
TL;DR: Examination of the underlying molecular mechanisms has shown that adiponectin treatment increases AMP-activated protein kinase (AMPK) phosphorylation and activity and increases the expression of tumor suppressor gene, L KB1 in breast cancer cells, highlighting a new role for LKB1 in adiponECTin action.
Abstract: Adiponectin is an adipocytokine involved in the pathogenesis of various obesity-related disorders. Also, it has been shown that adiponectin has therapeutic potential for metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. Adiponectin can modulate breast cancer cell growth and proliferation. Anti-metastatic effects of adiponectin have also been elucidated. It has been shown that adiponectin inhibits important metastatic properties such as adhesion, invasion and migration of breast cancer cells. Examination of the underlying molecular mechanisms has shown that adiponectin treatment increases AMP-activated protein kinase (AMPK) phosphorylation and activity. Adiponectin also increases phosphorylation of downstream target of AMPK, Acetyl-CoA Carboxylase (ACC) and decreases phosphorylation of p70S6 kinase (S6K). Importantly, adiponectin treatment increases the expression of tumor suppressor gene, LKB1 in breast cancer cells. LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, its biological functions including inhibition of adhesion, migration and invasion of breast cancer cells. Although further studies are required to analyze the effect of adiponectin on LKB1-AMPK-S6K axis, these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. These results highlight a new role for LKB1 in adiponectin action and may have significant implication for development of novel therapeutic options. Cancer research has largely focused on the molecular basis of oncogenic transformation and tumorigenesis for many years. Recent progress in cancer research has put the metastatic process at the center stage because higher metastatic potential of tumor cells is the major cause of mortality from solid tumors. Metastasis is a complex process that involves modulation of various molecular signaling networks. Tumor cells alter the microenvironment, attain greater cellular adhesion along with better ability to invade and migrate to gain access to circulation. These wandering tumor cells defy anoikis, survive in the circulation, exit into new permissive organ site and colonize distant organs. The microenvironment in which the tumor originates plays an important role in tumor initiation, progression and metastasis.
TL;DR: The goal is to identify the broad features of neural crest origins (developmentally) and migration (cellularly) using data from the zebrafish and Xenopus laevis in order to illuminate where general mechanisms appear to be in play, and equally importantly, where disparities in experimental results suggest areas of profitable study.
Abstract: The neural crest is an evolutionary adaptation, with roots in the formation of mesoderm. Modification of neural crest behavior has been is critical for the evolutionary diversification of the vertebrates and defects in neural crest underlie a range of human birth defects. There has been a tremendous increase in our knowledge of the molecular, cellular, and inductive interactions that converge on defining the neural crest and determining its behavior. While there is a temptation to look for simple models to explain neural crest behavior, the reality is that the system is complex in its circuitry. In this review, our goal is to identify the broad features of neural crest origins (developmentally) and migration (cellularly) using data from the zebrafish (teleost) and Xenopus laevis (tetrapod amphibian) in order to illuminate where general mechanisms appear to be in play, and equally importantly, where disparities in experimental results suggest areas of profitable study.
TL;DR: This study systematically explore the migratory and proliferative responses of human MSCs (hMSC) to chemokines expressed in MS lesions and shows that RANTES and IP-10 promote hMSC proliferation.
Abstract: Systemic delivery of multipotent mesenchymal stem cells (MSC) may be of benefit in the treatment of neurological diseases, including multiple sclerosis (MS). Certainly, animal studies have demonstrated functional benefits following MSC transplantation, although the mechanisms by which MSCs migrate to lesions and stimulate repair remain unknown. Chemokines stimulate migration in other settings. In this study, we systematically explore the migratory and proliferative responses of human MSCs (hMSC) to chemokines expressed in MS lesions. We demonstrate that these chemokines trigger hMSC migration. In addition, we show that RANTES and IP-10 promote hMSC proliferation.
TL;DR: Homodimerization of APP is driven by motifs present in the extracellular domain and possibly in the juxtamembrane and transmembrane (JM/TM) domains of the protein.
Abstract: Extensive research efforts have been conducted over the past decades to understand the processing of the Amyloid Precursor Protein (APP). APP cleavage leads to the production of the beta-amyloid peptide (Abeta), which is the major constituent of the amyloid core of senile plaques found in the brains of patients with Alzheimer's disease (AD). Abeta is produced by the sequential cleavage of APP by beta- and gamma-secretases. Cleavage of APP by gamma-secretase also generates the APP Intracellular C-terminal Domain (AICD) peptide, which might be involved in regulation of gene transcription. Up to now, our understanding of the mechanisms controlling APP processing has been elusive. Recently, APP was found to form homo- or hetero-complexes with the APP-like proteins (APLPs), which belong to the same family and share some important structural properties with receptors having a single membrane spanning domain. Homodimerization of APP is driven by motifs present in the extracellular domain and possibly in the juxtamembrane and transmembrane (JM/TM) domains of the protein. These striking observations raise important questions about APP processing and function: How and where is APP dimerizing? What is the role of dimerization in APP processing and function? Can dimerization be targeted by small molecule therapeutics?
TL;DR: The pseudopod tool is described and the first data based on the analysis of ~1000 Pseudopodia extended by Dictyostelium cells in the absence of external cues is presented.
Abstract: To understand movement of amoeboid cells we have developed an information tool that automatically detects protrusions of moving cells. The algorithm uses digitized cell recordings at a speed of ~1 image per second that are analyzed in three steps. In the first part, the outline of a cell is defined as a polygon of ~150 nodes, using the previously published Quimp2 program. By comparing the position of the nodes in place and time, each node contains information on position, local curvature and speed of movement. The second part uses rules for curvature and movement to define the position and time of start and end of a growing pseudopod. This part of the algorithm produces quantitative data on size, surface area, lifetime, frequency, and direction of pseudopod extension. The third part of the algorithm assigns qualitative properties to each pseudopod. It decides on the origin of a pseudopod as splitting of an existing pseudopod or as extension de novo. It also decides on the fate of each pseudopod as merged ...
TL;DR: A highly coordinated mechanism that regulates filopodia formation, adhesion, protein composition and force generation in a filopODia dependent step by step process is hypothesized.
Abstract: Filopodia are key structures within many cells that serve as sensors constantly probing the local environment. Although filopodia are involved in a number of different cellular processes, their function in migration is often analyzed with special focus on early processes of filopodia formation and the elucidation of filopodia molecular architecture. An increasing number of publications now describe the entire life cycle of filopodia, with analyses from the initial establishment of stable filopodium-substrate adhesion to their final integration into the approaching lamellipodium. We and others can now show the structural and functional dependence of lamellipodial focal adhesions as well as of force generation and transmission on filopodial focal complexes and filopodial actin bundles. These results were made possible by new high resolution imaging techniques as well as by recently developed elastomeric substrates and theoretical models. The data additionally provide strong evidence that formation of new fi...
TL;DR: The functional role of the recurrent genomic changes in lung tumors has been explored, which has led to a better understanding of cell growth, differentiation and apoptotic pathways.
Abstract: Lung cancer is a complex spectrum of diseases characterized by extensive genomic instability, which can be detected among both histological subtypes and different foci within a tumor. Conventional and cutting edge investigative technologies have uncovered scores of genomic changes in individual specimens that have been used to characterize specific molecular subtypes. Oncogenes with predominant roles in lung cancer include EGFR, MYC and RAS family members, PIK3CA, NKX2-1 and ALK; tumor suppressor genes include TP53, RB1, CDKN2, and a cluster of genes mapped at 3p. MicroRNA regulators also have been linked to lung cancer. The functional role of the recurrent genomic changes in lung tumors has been explored, which has led to a better understanding of cell growth, differentiation and apoptotic pathways. Additionally, this knowledge has supported the development of novel therapeutics and translational tools for selection of patients for personalized therapy.
TL;DR: The group showed that such a water channel through Lin7/beta catenin affects the organization of the cytoskeleton and proposed a model, which appears particularly intriguing since the use of AQP1 as target might be useful to modulate angiogenesis/vasculogenic mimicry.
Abstract: AQPs are water channel proteins. In particular, AQP1 was demonstrated to be involved in cell migration. According to the model proposed by Verkman and collaborators, AQP drives water influx, facilitating lamellipodia extension and cell migration. Investigating the possible connection between AQP1 and cytoskeleton, our group showed that such a water channel through Lin7/beta-catenin affects the organization of the cytoskeleton and proposed a model. All together, these data appear particularly intriguing since the use of AQP1 as target might be useful to modulate angiogenesis/vasculogenic mimicry.
TL;DR: Recent advances in understanding of prespecification during trunk NCC development are highlighted, highlighting recent advances in the understanding of target-derived signals emanating from the environment they migrate through.
Abstract: Neural crest cells (NCCs) are migratory cells that delaminate from the neural tube early in development and then disseminate throughout the embryo to give rise to a wide variety of cell types that are key to the vertebrate body plan. During their journey from the neural tube to their peripheral targets, NCCs progressively differentiate, raising the question when the fate of an individual NCC is sealed. One hypothesis suggests that the fate of a NCC is specified by target-derived signals emanating from the environment they migrate through, while another hypothesis proposes that NCCs are already specified to differentiate along select lineages at the time they are born in the neural tube, with environmental signals helping them to realize their prespecified fate potential. Alternatively, both mechanisms may cooperate to drive NCC diversity. This review highlights recent advances in our understanding of prespecification during trunk NCC development.