Saturday, 23rd June 2018
Cell Biology and Immunology
    Functional interactins between tetraspanin CD9 and cell adhesion molecules






Carlos Cabañas







Research summary:



Confocal microscopy analysis of the co-localization between the adhesion molecule ALCAM/CD166 and the tetraspanin CD9 in Jurkat T cells, CD9-transfected Raji B cells and BLM melanoma cells. Partial co-localization of these molecules is observed on the plasma membrane of the three cell types. Interestingly, the areas of co-localization between CD9 and ALCAM on lymphoid cells are distributed following a patched pattern while on the adherent BLM melanoma cells co-localization is particularly enriched in cell-cell contacts.



The tetraspanin CD9 displays a high ability to interact with other surface proteins in several types of cells. Through these interactions, CD9 regulates key cellular processes such as adhesion, migration, invasion and proliferation.

ADAM17/TACE is protease responsible for ectodomain "shedding" of a large number of cell surface proteins that are critically involved in development, growth, adhesion, differentiation, and migration of leukocytes and tumor cells. ADAM-17/TACE is particularly important in the regulation of cell adhesion through the shedding of different adhesion molecules that either belong to the immunoglobulin superfamily (ICAM-1, VCAM-1, NCAM, L1CAM AND ALCAM) or to other families of adhesion receptors (CD44 and L-selectin).

ALCAM/CD166 is a transmembrane glycoprotein of 110 kDa with five Ig-type domains in its extracellular region, a single transmembrane region and a short intracytoplasmic tail. ALCAM mediates cell adhesion through homophilic (ALCAM-ALCAM) as well as heterophilic (ALCAM-CD6) interactions, and has been implicated in the invasive growth and metastasis of different types of tumors (melanomas and breast, prostate, ovary and colorectal carcinomas). ALCAM can be cleaved at its juxtamembrane extracellular region by ADAM-17/TACE, causing the release of a 96 kDa soluble form (sALCAM). The circulating levels of sALCAM are elevated in patients of different types of cancers, which suggests the implication of this molecule in the motility and invasion of malignant cells.

Our recent results have demonstrated that CD9 is capable to regulate the adhesion of tumoral cells through a dual mechanism. On the one hand, this tetraspanin induces the aggregation of different adhesion molecules though specific interactions inducing their recruitment into cell surface microdomains termed TEMs (Tetraspanin-Enriched Microdomains), which in turn induces changes in the avidity of these molecules for their ligands. Additionally, CD9 negatively regulates the proteolytic activity of ADAM-17/TACE and through this effect is able to control the balance between the transmembrane and soluble forms (and hence the activity) of different proteins involved in cell adhesion and inflammation, including TNF-α, ICAM-1 and ALCAM.


Relevant publications:

  • Gutiérrez-López, M.D., Gilsanz, A., Yánez-Mó, M., Ovalle, S., Lafuente, M.E., Domínguez, C., Monk, P.N., González-Alvaro, I., Sánchez-Madrid, F., and Cabañas, C. (2011). The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9. Cellular and Molecular Life Sciences 68:3275-3292.
  • Yánez-Mó, M., Sánchez-Madrid, F. and Cabañas C. (2011). Membrane proteases and tetraspanins. Biochemical Society Transactions 39:541-546.
  • Hernández-Varas, P., Coló, G.P., Bartolomé, R.A., Paterson, A., Medraño-Fernández, I., Cabañas, C., Sánchez-Mateos, P., Lafuente, E.M., Boussiotis, V.A., Strömblad, S. and Teixidó, J. (2011). Rap1-GTP-interacting adaptor molecule (RIAM) protein controls invasion and growth of melanoma cells. Journal of Biological Chemistry 286:18492-18504.
  • Yáñez-Mó, M., Gutiérrez-López, M.D., and Cabañas, C. (2011). Functional interplay between tetraspanins and proteases. Cellular and Molecular Life Sciences 68:3323-35.
  • Rossi, E., Langa, C., Gilsanz, A., Blanco, F.J., Ayllón, J., Villar, E., Botella, L.M., Cabañas, C., Shaw, M., and Bernabeu, C. (2012). Characterization of chicken endoglin, a member of the zona pellucida family of proteins, and its tissue expression. Gene 491:31-9


Doctoral Theses:

Iria Medraño Fernández (2012). Papel de la proteína adaptadora RIAM en la fagocitosis mediada por complemento. Universidad Complutense de Madrid. Directores: Dra. Mª Esther Lafuente y Dr. Carlos Cabañas.

Álvaro Gilsanz Cáceres (2012). La tetraspanina CD9 regula la función de la metaloproteasa ADAM17/TACE y de su sustrato ALCAM. Universidad Complutense de Madrid. Director: Dr. Carlos Cabañas.