The adaptor molecule CIN85 regulates Syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway.
Triggering of mast cells and basophils by IgE and Ag initiates a cascade of biochemical events that lead to cell degranulation and the release of allergic mediators. Receptor aggregation also induces a series of biochemical events capable of limiting FcepsilonRI-triggered signals and functional responses. Relevant to this, we have recently ... demonstrated that Cbl-interacting 85-kDa protein (CIN85), a multiadaptor protein mainly involved in the process of endocytosis and vesicle trafficking, regulates the Ag-dependent endocytosis of the IgE receptor, with consequent impairment of FcepsilonRI-mediated cell degranulation. The purpose of this study was to further investigate whether CIN85 could alter the FcepsilonRI-mediated signaling by affecting the activity and/or expression of molecules directly implicated in signal propagation. We found that CIN85 overexpression inhibits the FcepsilonRI-induced tyrosine phosphorylation of phospholipase Cgamma, thus altering calcium mobilization. This functional defect is associated with a substantial decrease of Syk protein levels, which are restored by the use of selective proteasome inhibitors, and it is mainly due to the action of the ubiquitin ligase c-Cbl. Furthermore, coimmunoprecipitation experiments demonstrate that CIN85 overexpression limits the ability of Cbl to bind suppressor of TCR signaling 1 (Sts1), a negative regulator of Cbl functions, while CIN85 knockdown favors the formation of Cbl/Sts1 complexes. Altogether, our findings support a new role for CIN85 in regulating Syk protein levels in RBL-2H3 cells through the activation of the ubiquitin-proteasome pathway and provide a mechanism for this regulation involving c-Cbl ligase activity.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Antigens, Basophils, Calcium Signaling, Cell Degranulation, Cell Line, Endocytosis, Gene Expression, Humans, Immunoglobulin A, Intracellular Signaling Peptides and Proteins, Mast Cells, Neoplasm Proteins, Nerve Tissue Proteins, Phospholipase C gamma, Phosphorylation, Proteasome Endopeptidase Complex, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Rats, Receptors, Antigen, T-Cell, Receptors, IgE, Ubiquitin, Ubiquitin-Protein Ligases
Adaptor Proteins, Signal Transducing, Animals, Antigens, Basophils, Calcium Signaling, Cell Degranulation, Cell Line, Endocytosis, Gene Expression, Humans, Immunoglobulin A, Intracellular Signaling Peptides and Proteins, Mast Cells, Neoplasm Proteins, Nerve Tissue Proteins, Phospholipase C gamma, Phosphorylation, Proteasome Endopeptidase Complex, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Rats, Receptors, Antigen, T-Cell, Receptors, IgE, Ubiquitin, Ubiquitin-Protein Ligases
J. Immunol.
Date: Aug. 15, 2007
PubMed ID: 17675467
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