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Syk-dependent regulation of Hrs phosphorylation and ubiquitination upon FcεRI engagement: impact on Hrs membrane/cytosol localization.

Abstract : Several lines of evidence suggest that Syk controls immune receptor endocytic trafficking. However, the Syk substrates that regulate this process are not currently known. Here, we demonstrate that Syk knockdown prevents the trafficking of engaged high affinity IgE receptor (FcεRI) to a degradative compartment in mast cells. We then concentrate our attention on hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) as potential Syk substrate, since it serves as critical regulator for FcεRI entry into lysosomes. We show that Hrs undergoes antigen-dependent tyrosine phosphorylation and ubiquitination, and identify Syk as the kinase responsible for Hrs phosphorylation. Syk was also required for Hrs ubiquitination catalyzed by c-Cbl E3 ligase. Syk-dependent regulation of Hrs covalent modifications, without affecting protein stability, controlled Hrs localization. The majority of phosphorylated Hrs forms were observed only in membrane compartments, whereas ubiquitinated Hrs was predominantly cytosolic, suggesting that both modifications might impact on Hrs function. Together, these findings provide a major step forward in understanding how Syk orchestrates endocytosis of engaged immune receptors.
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Francesca Gasparrini, Rosa Molfetta, Linda Quatrini, Luigi Frati, Angela Santoni, et al.. Syk-dependent regulation of Hrs phosphorylation and ubiquitination upon FcεRI engagement: impact on Hrs membrane/cytosol localization.. European Journal of Immunology, Wiley-VCH Verlag, 2012, 42 (10), pp.2744-53. ⟨10.1002/eji.201142278⟩. ⟨pasteur-00947738⟩

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