Thesis presented October 27, 2014
Abstract: The arrestin clan represents a large group of adaptor proteins which includes the canonical arrestins - β-arrestins and visual arrestins – well described for their role in the regulation of membrane receptors coupled to heterotrimeric G-proteins and associated signaling as well as
arrestin-like proteins identified more recently that seem to share functions in the regulation and trafficking of membrane cargoes. This work focused on the study of the
arrestin-like protein AdcA of
Dictyostelium discoideum, to determine the functional role of this atypical member. In addition to the arrestin module common to all the members of the arrestin family, AdcA harbors a FYVE domain responsible for its association to the endocytic pathway, a C-terminal tyrosine-rich domain and an N-terminal extension rich in histidine residues mediating its oligomerization. I have established that AdcA responds to a variety of stresses such as hyperosmolarity by a massive multi-phosphorylation of the protein. Sensitivity of AdcA to changes in F-actin polymerization status suggests a link between the signaling cascade leading to AdcA phosphorylation and the actin cytoskeleton. In conditions of moderate stress, AdcA response is transient and its dephosphorylation depends on the transcription factor STATc and correlates with cell adaptation to the stress conditions. This post-translational modification of AdcA could modulate its activity and optimize the cell response to stress. In parallel, the functional characterization of a partner of AdcA, the protein FrmC, has been undertaken. This so-far uncharacterized protein presents a multimodular structure with a FERM domain able to bind F-actin
in vitro and several leucine-rich repeats (LRR). I have shown that FrmC is recruited to the plasma membrane and is involved in cell- substrate adhesion. In addition, disruption of FrmC affects cell adaptation and AdcA response in conditions of hyperosmotic stress.
Keywords:Dictyostelium, arrestin, AdcA, hyperosmotic stress, STATc, FERM domain containing protein, actin, adhesion
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