Cell junction | EPFL Graph Search

Cell junctions or junctional complexes, are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together. Cell junctions are also especially important in enabling communication between neighboring cells via specialized protein complexes called communicating (gap) junctions. Cell junctions are also important in reducing stress placed upon cells. In plants, similar communication channels are known as plasmodesmata, and in fungi they are called septal pores. Types In vertebrates, there are three major types of cell junction: *Adherens junctions, desmosomes and hemidesmosomes (anchoring junc

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and beta-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and beta-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/beta-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer. Oncogene (2012) 31, 48-59; doi: 10.1038/onc.2011.218; published online 13 June 2011

2012

Structure and function of the olfactory bulb microcircuit

Michele Pignatelli

The aim of this study is to contribute to understand the physiology of the Olfactory System through detailed microcircuit investigation, adopting advanced electrophysiological and anatomical techniques. Multiple patch clamp recordings allow understanding the structural foundations supporting the network architecture, the biophysical rules adopted by the microcircuit connectivity and the fine dynamic of the synaptic transmission. The study focuses on the Olfactory Bulb microcircuit as a first neuronal processor of sensory inputs. The excitatory elements of the Olfactory Bulb microcircuit are anatomically defined by affiliation to the same receptive field: the Glomerulus. A correlated subthreshold activity between microcircuit elements defines the physiological signature of the microcircuit. We experimentally addressed three fundamental issues: origin of the correlated subthreshold activity, connectivity rules and dynamic of the synaptic transmission. In the first study we attribute the origin of correlated subthreshold activity to a class of pacemaker cells responsible for the synchronization of the population onset and acting therefore as a timer of the microcircuit response. In the second study we investigated the connectivity rules supporting the interaction between excitatory cells. The tight apposition between gap junctions and chemical synapses on the excitatory cells dendrites allows gap junctions to propagate postsynaptic potentials toward surrounding compartments. The result of the propagation is represented by an enhancement in the amplification of the sensory information and an increase in the speed of the reaction time. In the third study we extensively analyzed the mechanisms of the synaptic transmission and the activity dependent properties of synapses, revealing a potential role for the short-term plasticity in the development of the sensory processing. The results of our investigation are going to constitute the foundation of a database available for high definition multi-compartmental modeling of the Olfactory Bulb network.

EPFL2009

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Yan Agalarov, Esther Bovay, Mauro Delorenzi, Nadine Zangger

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

American Society for Clinical Investigation2015

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

2012

Structure and function of the olfactory bulb microcircuit

Michele Pignatelli

EPFL2009