Proteolytic Enzymes Clustered in Specialized Plasma-Membrane Domains Drive Endothelial Cells’ Migration

Information from studies of embryonic nephrons and established renal tubular cell lines in culture can be integrated to derive a picture of how the renal tubule develops and regenerates after acute injury. During development, the formation of a morphologically polarized epithelium from committed nephric mesenchymal cells requires an external signal for mitogenesis and differentiation. Polypeptide growth factors, in some cases mediated through oncogene expression, act in an autocrine or paracrine fashion to stimulate the production of extracellular matrix proteins that probably provide the earliest orientation signal for the cell. Interaction of these proteins with cell surface receptors leads to early organization of the cytoskeletal actin network, which is the major scaffolding for further differentiation and for definition of plasma membrane domains. The formation of cell-cell contacts via specialized adhesion molecules integrates the epithelium into a polarized monolayer and maintains its fence function, i.e., separation of plasma membrane domains. Microtubules probably participate in the delivery of vesicles to specific plasma membrane domains and in the spatial organization of intracellular organelles. Following acute renal injury, this sequence of events appears to be reversed, resulting in partial or complete loss of differentiated features. Regeneration seems to follow the same pattern of sequential differentiation steps as nephrogenesis. The integrity of the epithelium is restored by reestablishing only those stages of differentiation that have been lost. Where cell death occurs, mitogenesis in adjacent cells restores the continuity of the epithelium and the entire sequence of differentiation events is initiated in the newly generated cells.

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MYADM controls endothelial barrier function through ERM-dependent regulation of ICAM-1 expression

Molecular Biology of the Cell ◽

10.1091/mbc.e11-11-0914 ◽

2013 ◽

Vol 24 (4) ◽

pp. 483-494 ◽

Cited By ~ 17

Author(s):

Juan F. Aranda ◽

Natalia Reglero-Real ◽

Beatriz Marcos-Ramiro ◽

Ana Ruiz-Sáenz ◽

Laura Fernández-Martín ◽

...

Keyword(s):

Endothelial Cells ◽

Plasma Membrane ◽

Inflammatory Response ◽

Barrier Function ◽

Leukocyte Adhesion ◽

Cell Junctions ◽

Membrane Domains ◽

Filamentous Actin ◽

Cytokine Tumor Necrosis Factor ◽

Factor Α

The endothelium maintains a barrier between blood and tissue that becomes more permeable during inflammation. Membrane rafts are ordered assemblies of cholesterol, glycolipids, and proteins that modulate proinflammatory cell signaling and barrier function. In epithelial cells, the MAL family members MAL, MAL2, and myeloid-associated differentiation marker (MYADM) regulate the function and dynamics of ordered membrane domains. We analyzed the expression of these three proteins in human endothelial cells and found that only MYADM is expressed. MYADM was confined in ordered domains at the plasma membrane, where it partially colocalized with filamentous actin and cell–cell junctions. Small interfering RNA (siRNA)-mediated MYADM knockdown increased permeability, ICAM-1 expression, and leukocyte adhesion, all of which are features of an inflammatory response. Barrier function decrease in MYADM-silenced cells was dependent on ICAM-1 expression. Membrane domains and the underlying actin cytoskeleton can regulate each other and are connected by ezrin, radixin, and moesin (ERM) proteins. In endothelial cells, MYADM knockdown induced ERM activation. Triple-ERM knockdown partially inhibited ICAM-1 increase induced by MYADM siRNA. Importantly, ERM knockdown also reduced ICAM-1 expression in response to the proinflammatory cytokine tumor necrosis factor-α. MYADM therefore regulates the connection between the plasma membrane and the cortical cytoskeleton and so can control the endothelial inflammatory response.

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