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Caracterización de nuevos miembros de la familia MAL de proteínas

AuthorsAranda, Juan Francisco
AdvisorAlonso, Miguel A.
KeywordsTransporte biológico
Issue Date2008
PublisherUniversidad Autónoma de Madrid
AbstractCell polarity is characterized by morphological and functional cell asymmetry that allows the segregation of protein machinery in membrane domains. Cell polarity can be constitutive, i.e. in the epithelium, or transient, as during migration. There are two main mechanisms that contribute to establish cell polarity. First, cell membranes have the ability to form domains of specific lipid composition that selectively cluster proteins in order to regulate signalling processes. These domains are heterogeneous and are commonly known as membrane or lipid rafts. Second, the underlying cytoskeleton contributes also to protein segregation by interacting directly with transmembrane proteins and/or modifying the distribution of membrane rafts. Membrane rafts and the actin cytoskeleton act co-ordinately during processes that require polarization, namely cell motility, but the underlying mechanism regulating this coordination is poorly understood. This is partly because of the fact that the protein machinery that regulates the function of membrane rafts is almost unknown. Amongst the proteins candidates to constitute the scaffold of membrane rafts are the MAL family proteins. MAL and MAL2 have been characterized as raft components of the apical machinery of transport in epithelial cells and transcytotic transport in hepatic cells, respectively. The work presented here is focused on a new member of the MAL family called myeloid-associated differentiation marker protein (MYADM/bigMAL1). This protein is also an integral component of membrane rafts. In contrast to MAL and MAL2, bigMAL1 is ubiquitously expressed and initial data shows that bigMAL1 localizes to actin-rich structures in cell-to-cell junctions in confluent epithelial monolayers and to lamellipodium-like structures in migrating cells, suggesting a role during general processes of polarization that are not restricted to specialized cell types. Functional analysis using a siRNA-based approach suggests that: 1) bigMAL1 regulates cell morphology and polarization and migration in various cell types and 2) bigMAL1 functionally interacts with components that regulate the actin cytoskeleton such as RhoGTPases Rac and Rho, because of their activation state are affected in the absence of bigMAL1. Therefore, bigMAL1 is a good candidate to link membrane rafts and the actin cytoskeleton during cell motility. Finally, bigMAL1 is highly expressed in endothelial cells. Endothelial cells regulate the homeostasis of blood vessels and, in particular, play a very important role in promoting the transmigration of leucocytes from the bloodstream towards inflammatory foci. The family of proteins Ezrin Radixin Moesin (ERM) are connectors between the endothelial transmembrane surface receptors that regulate leucocyte transmigration and the actin cytoskeleton. ERMs are activated by phosphorylation of threonine in its C-terminal domain by ROCK. The absence of bigMAL1 upregulates the activity of the Rho GTPase RhoA that subsequently activates the kinase ROCK. Reduction of bigMAL1 in endothelial cells also increases phosphorylation of ERM probably due to the effect of active RhoA on ROCK. As a consequence, the ERM associated surface receptor ICAM-1, which mediates leucocyte transmigration also appears augmented. ICAM-1 mediates the firm adhesion of leucocytes to the endothelium by interacting with beta2 integrins. In conclusion, bigMAL1 plays a general role regulating Rho GTPases in different cell types. In endothelial cells, where bigMAL1 is abundant this regulation has an effect of the activation of the ERM proteins that regulate the dynamics of important adhesion surface receptors such as ICAM-1 on the plasma membrane.
DescriptionTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura 22-02-2008
Appears in Collections:(CBM) Tesis
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