Functional interactions between tetraspanin CD9 and cell adhesion molecules

Research summary:

Tetraspanins are highly conserved membrane proteins that function as membrane-organizers and control fundamental cell functions, including adhesion, migration and proliferation. The tetraspanin CD9 specifically associates with different adhesion receptors of the immunoglobulin and integrin families in tetraspanin-enriched microdomains (TEMs). Through these interactions, CD9 exerts important regulatory effects on the function of associated adhesion molecules. Our group has reported that CD9 associates directly with the metalloproteinase ADAM17 on the surface of different types of cells, exerting an inhibitory effect on ADAM17 sheddase activity against a variety of its substrates. Interactions of integrin α5β1 with ADAM17 may occur among molecules expressed on the same cell (cis) or on different cells (trans), with the latter reported to support cell-cell adhesion events. Interestingly, the interaction between integrin α5β1 and the disintegrin domain of ADAM17 has been shown to cause the inhibition of both the adhesive capacity of the integrin (i.e. its ability to bind its ligands) as well as of ADAM17 metalloproteinase activity due to steric hindrance leading to decreased accessibility of its catalytic site for the substrate. In contrast, stimuli that promote the dissociation of the α5β1-ADAM17 complex induce the activation of ADAM17 sheddase activity and increase integrin-mediated cell adhesion. Interestingly, the expression of CD9 on the cell surface abrogates integrin α5β1-mediated cell adhesion to its ligands fibronectin and ADAM17-Fc. In situ proximity ligation assays (PLA) and biochemical experiments based on co-immunoprecipitation collectively revealed that the mechanism by which CD9 inhibits α5β1-mediated cell adhesion involves the reinforcement of cis interactions between ADAM17 and α5β1 on the cell surface, which takes place without alteration in α5β1 integrin affinity but is evidenced by changes in the organization of integrin molecules at the plasma membrane.

Exosomes are a type of extracellular vesicles (EVs) of endocytic origin which serve important intercellular communication functions. Exosomes are produced and released by a large variety of donor cells in the organism and contain a specific cargo of lipids, proteins, miRNAs, mRNAs and DNA which, upon their selective binding and/or uptake can modify the phenotype and trigger a functional response in target cells. Tetraspanins are very abundantly expressed on the surface of different types of extracellular vesicles (EVs), including exosomes, and many research groups consider these proteins as the best markers for these EVs. Our group is currently investigating the role of CD9 as a regulator of adhesion molecules and metalloproteinases involved in the binding and/or uptake of exosomes by target cells.

Image

Direct interaction between CD9 and integrin LFA-1 revealed by PLA. (A) Proximity Ligation Assay (PLA) of the molecular association of CD9 with CD147 (negative control) and of CD9 with integrin LFA-1 (positive control) on THP1 macrophage-like cells. (B) The graph represents the quantification PLA signal from panel (A) (mean of PLA/dots from different micrographic fields analyzed by unpaired t test. ****p < 0.0001).

Image


* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Bezos CarmonaTamara1254513GJ-AI_Tit. Sup. Actividades Técn. y Prof.GP1
Cabañas GutiérrezCarlos1254513ccabanas(at)cbm.csic.esE. Investigadores Científicos de Organismos Públicos
Clares PedreroIrene1254513irene.clares(at)cbm.csic.esGJ-AI y TL_Titulado Sup. Actividades Técn. y Prof.GP1
Fernández RodríguezAna Mª663930632Estudiante TFM
Melones DelgadoAlejandro1254513Estudiante TFG

Relevant publications:

  • Torres-Gómez A, Cardeñes B, Díez-Sainz E, Lafuente EM, & Cabañas C. (2020) Functional Integrin Regulation Through Interactions with Tetraspanin CD9. Methods in Molecular Biology 2217:47-56. (doi: 10.1007/978-1-0716-0962-0_5).
  • Torres-Gomez A, Cabañas C, & Lafuente EM. (2020). Phagocytic Integrins: Activation and Signaling. Frontiers in Immunology 11:738. (doi: 10.3389/fimmu.2020.00738).
  • Torres-Gomez A, Sanchez-Trincado JL, Toribio V, Torres-Ruiz R, Rodríguez-Perales S, Yáñez-Mó M, Reche PA, Cabañas C, & Lafuente EM. (2020). RIAM-VASP Module Relays Integrin Complement Receptors in Outside-In Signaling Driving Particle Engulfment. Cells 9:1166. (doi: 10.3390/cells9051166).
  • Mikuličić S, Fritzen A, Scheffer K, Strunk J, Cabañas C, Sperrhacke M, Reiss K, & Florin L. (2020). Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway. Medical Microbiology and Immunology 209:461-471. (doi: 10.1007/s00430-020-00671-5).
  • Cabañas, C,Yáñez-Mó, M, & van Spriel, A. (2019). Functional relevance of tetraspanins in the immune system. Frontiers in Immunology 10:1714. (doi: 10.3389/fimmu.2019.01714).
  • Toribio V, Morales S, López-Martín S, Cardeñes B, Cabañas C, & Yáñez-Mó M. (2019). Development of a quantitative method to measure EV uptake. Scientific Reports 9:10522. (doi: 10.1038/s41598-019-47023-9).

Doctoral theses:

  • Doctorando: Yesenia Machado Pineda (Ftad. Biología, UCM).
    Título: Caracterización de anticuerpos monoclonales funcionales específicos de ADAM-17
    Fecha: Noviembre 2017
    Calificación: Sobresaliente cum laude
  • Doctorando: Raquel Reyes Manzanas (Ftad. Biología, UAM).
    Título: La tetraspanina CD9 regula la capacidad adhesiva de la integrina leucocitaria LFA-1
    Fecha: Enero de 2016
    Calificación: Sobresaliente cum laude
  • 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.

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: