Rudolf Mößbauer Colloquium with Benny Geiger (Weizmann Institute of Science)

Rudolf Mößbauer Colloquium with Benny Geiger (Weizmann Institute of Science)

  • Date: Nov 26, 2018
  • Time: 15:00 - 16:00
  • Location: MPI for Medical Research
  • Room: Seminar Room A/B
  • Host: MPI for Medical Research
Rudolf Mößbauer Colloquium with Benny Geiger (Weizmann Institute of Science)
Multi-scale view of cell adhesion-mediated mechanosensitivity: From mollecules to cells to tissues

Nanoscale: Focal adhesions (FAs) are multi-protein complexes that connect the actin cytoskeleton to the extracellular matrix, via integrin receptors. The growth, stability and adhesive functionality of these structures are tightly regulated by mechanical stress, yet, despite the extensive characterization of the integrin adhesome, the mechanisms underlying FA mechanosensitivity are still poorly understood. One of the key candidates for regulating FA-associated mechanosensing is vinculin, a prominent FA component, which was proposed to possess either closed (“auto-inhibited”) or open ("active") conformations. However, a direct demonstration of the nature of conformational transition between the two states is still absent. We combined mass spectrometry, structural and cell biological approaches to probe the transition from the auto-inhibited to the active states, and to determine its effects on FA structure and dynamics. We further show here that the closed to open transition requires two sequential steps that can differentially regulate FA growth and stability.

Microscale: Important cellular structures that drive the invasion of metastatic cancer cells are invadopodia that contain an actin core that interacts with integrin-containing matrix adhesions, at its basal end, while its apical end, pushes against the nucleus and indents it. Blocking of invadopodia formation by microtubule- or src-inhibitors, leads to the disappearance of these nuclear indentations. Based on the indentation profile and the viscoelastic properties of the nucleus, the force applied by invadopodia, to the extracellular matrix is very high, in the range of tens of nanoNewton/µm2. We will discuss the mechanical regulation of invadopodia stability and the roles of the tyrosine kinome in their formation and their involvement in cancer invasion and metastasis.

Macroscale: Gut barrier function represents a critical intestinal mechanism enabling, on the one hand, an efficient nutrient and water absorption in the small and large intestine, respectively, and effectively block the indiscriminate influx of immune-modulatory stimulants and of bacteria and bacterial components, across the gut wall, risking in initiation of uncontrolled inflammation, including Inflammatory Bowel Disease. The sealing of the gut lumen is achieved by a thin and coherent sheet of Intestinal Epithelial Cells, which are firmly attached, via their basal aspects, to the underlying basement membrane, and are interacting with neighbouring cells via a robust junctional complex, that consist of apical tight junction (TJs) and cytoskeleton-reinforced adherens junctions and desmosomes. We discovered that key TJ disruptors, induce cell contraction, while prominent junction stabilizers block actomyosin contractility. We will address the molecular basis for the mechano-regulation of cell adhesions, and discuss their involvement in the long-range regulation of the gut function

Go to Editor View