Friday, 15th December 2017
Cell Biology and Immunology
         Cytoskeleton-plasma membrane interactions





Isabel Correas Hornero




Research summary:

Cell morphology and tissue organization are maintained through multiple interactions between lipids and proteins from the plasma membrane and the underlying cytoskeleton. The coordination between surface membranes and different cytoskeletal networks is essential for processes such as cell migration, polarity, epithelial and endothelial barrier stability, cell division or intracellular vesicular transport.

In recent years we have been interested in investigating the role of proteins that regulate plasma membrane and/or cytoskeletal organization in different cellular events. We have been studying the role in cell migration of the 4.1 family of proteins, which connect subcortical cytoskeleton to lipids and membranes through FERM (four-point-one, ezrin, radixin, moesin) domains.



Protein 4.1R at the plasma membrane – cytoskeleton interface. A) ECV304 cells stained for 4.1R (green), microtubule plus-end protein EB1 (red) and a-tubulin (blue). B) Stage 9 egg chamber from Drosophila melanogaster, stained for 4.1/Coracle (green), membrane targeted GFP (red) and DAPI (blue). C) Eye-antennal imaginal disc from D. melanogaster third instar larva, stained for 4.1/Coracle (green), neural marker ELAV (red) and DAPI (blue).




ERM proteins regulate cell-cell junction stability. (A) Active phosphorylated ERM proteins are enriched in cell-cell contacts in endothelial cells (arrow). (B) Overexpression of a constitutively active mutant moesin (Moesin T>D) induces gap opening at cell-cell junctions (arrows). (More in Aranda et al. MBoC 2012). (C) Reticular junctions in human endothelial cells. Reticular structures at cell-cell overlapping contacts regulate endothelial cell permeability and are dispersed in response to TNF-a. Reticular Adherens Junctions (b-catenin) are interspersed in PECAM-1 tubular structures, as revealed by super resolution confocal microscopy (STED). (More in Fernandez-Martín et al. ATVB. 2012).



During the period 2011-2012 we have found that the protein 4.1R regulates cell migration and polarity by recruiting IQGAP1 to cell lamellipodia. In addition, 4.1R also controls the dynamics of microtubules and cortical platforms, membrane domains that connect microtubules to the plasma membrane in contact with the extracellular matrix. Collectively, our work unveils an essential role for 4.1R as a scaffolding protein at the cell leading edge. In parallel studies we have started the functional characterization of Coracle, the only protein 4.1 ortholog in Drosophila melanogaster.

A paradigmatic example of the importance of the membrane-cytoskeleton crosstalk is the maintenance of endothelial barrier integrity and its disruption in response to inflammation. In these two years we have characterized an unique organization of endothelial Adherens Junctions, called reticular, which controls the endothelial barrier and mediates the increase in permeability induced by the proinflammatory cytokine TNF-a It is of note that this permeability alteration is caused by activation of the 4.1 family members Ezrin, Radixin and Moesin at cell-cell borders.

Relevant publications:

  • Ruiz-Saenz, A., Kremer, L., Alonso, M.A., Millan, J., and Correas, I. (2011). Protein 4.1R regulates cell migration and IQGAP1 recruitment to the leading edge. J. Cell Sci. 124, 2529-2538.
  • Aranda, J.F., Reglero-Real, N., Kremer, L., Marcos-Ramiro, B., Ruiz-Saenz, A., Calvo, M., Enrich, C., Correas, I., Millan, J.*, and Alonso, M.A.* (2011). MYADM regulates Rac1 targeting to ordered membranes required for cell spreading and migration. Mol. Biol. Cell 22, 1252-1262.
  • Fernandez-Martin, L., Marcos-Ramiro, B., Bigarella, C.L., Graupera, M., Cain, R.J., Reglero-Real, N., Jimenez, A., Cernuda-Morollon, E., Correas, I., Cox, S., Ridley, A.J., and Millan, J. (2012). Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Arterioscler. Thromb. Vasc. Biol. 32, e90-e102.
  • Andres-Delgado, L., Anton, O.M., Bartolini, F., Ruiz-Saenz, A., Correas, I., Gundersen, G.G., and Alonso, M.A. (2012). INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells. J. Cell Biol. 198, 1025-1037.
  • Reglero-Real, N., Marcos-Ramiro, B., and Millan, J. (2012). Endothelial membrane reorganization during leukocyte extravasation. Cell Mol. Life Sci. 69, 3079-3099.


Doctoral Theses:

Ana Ruiz Sáenz (2011). La proteína 4.1R regula la organización del citoesqueleto de tubulina y la migración celular. Universidad Autónoma de Madrid. Director: Isabel Correas.