The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

Department of Experimental Medicine, Institute Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome, Italy.
The Journal of Immunology (Impact Factor: 4.92). 09/2007; 179(4):2089-96. DOI: 10.4049/jimmunol.179.4.2089
Source: PubMed


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.

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    • "Other ITAM-containing FcRs, such as FcεRI, can trigger both activating and inhibitory signals, thus contributing to their own, autonomous control (7, 11). In this case, the negative signal involves the coordinated action of adaptors (12–14), phosphatases (15, 16), and ubiquitin ligases (17–19) that limit the intensity and duration of positive signals, thus modulating cellular functions. "
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    • "Cbl expression is enriched in the podosome belt in osteoclasts at sites of cell attachment and as a result c-Cbl-/- osteoclasts have impaired motility [48]. CIN85 overexpression decreases intracellular calcium signaling and decreases PLCγ1 and 2 phosphorylation [49]. "
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    • "Thus, mutant B cells display a selective partial defect in BCR coupling to IKK signaling pathway. Previous studies with the transformed RBL-2H3 mast cell line showed that overexpression of CIN85 decreases the Syk protein level and enhances FcRI-mediated endocytosis (Peruzzi et al., 2007). Thus, we made a point of carefully checking the Syk protein level in mutant and control B cells but detected no significant difference (Fig. S5 A). "
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    ABSTRACT: CIN85, an adaptor protein which binds the C-terminal domain of tyrosine phosphorylated Cbl and Cbl-b, has been thought to be involved in the internalization and subsequent degradation of receptors. However, its physiological function remains unclear. To determine its role in B cells, we used Mb1-cre to generate mice with a B cell-specific deletion of CIN85. These mice had impaired T cell-independent type II antibody responses in vivo and diminished IKK-β activation and cellular responses to B cell receptor (BCR) cross-linking in vitro. Introduction of a constitutively active IKK-β construct corrected the defective antibody responses as well as cellular responses in the mutant mice. Together, our results suggest that CIN85 links the BCR to IKK-β activation, thereby contributing to T cell-independent immune responses.
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