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Department of Experimental Medicine, Institute Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza," Rome, Italy
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 Fc
RI-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 FcRI-mediated cell degranulation. The purpose of this study was to further investigate whether CIN85 could alter the FcRI-mediated signaling by affecting the activity and/or expression of molecules directly implicated in signal propagation. We found that CIN85 overexpression inhibits the FcRI-induced tyrosine phosphorylation of phospholipase C
, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was partially supported by grants from Italian Association for Cancer Research, Ministero dell’Istruzione, dell’Università e della Ricerca and the Centre of Excellence in Molecular Biology and Medicine.
2 G.P. and R.M. contributed equally to this work.
3 Current address: Department of Histology and Medical Embryology, University "La Sapienza," Rome, Italy.
4 Address correspondence and reprint requests to Dr. Rossella Paolini, Department of Experimental Medicine, University "La Sapienza," Viale Regina Elena 324, Rome, Italy. E-mail address: rossella.paolini{at}uniroma1.it
5 Abbreviations used in this paper: PTK, protein tyrosine kinase; anti-pTyr, anti-phosphotyrosine; Ub, ubiquitin; CIN85, Cbl-interacting 85-kDa protein; SH3, Src homology 3; WT, wild type; PLC, phospholipase C; HSA, human serum albumin; [Ca2+]i, intracellular calcium ion concentration; RT-Q-PCR, real-time quantitative PCR; siRNA, small interfering RNA; PCc, C-terminal proline-rich and coiled coil; Sts, suppressor of TCR signaling.
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  S. Ishmael and D. MacGlashan Jr. Early signal protein expression profiles in basophils: a population study J. Leukoc. Biol., August 1, 2009; 86(2): 313 - 325. [Abstract] [Full Text] [PDF]
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