The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway

Giovanna Peruzzi, Rosa Molfetta, Francesca Gasparrini, Laura Vian, Stefania Morrone, Mario Piccoli, Luigi Frati, Angela Santoni, Rossella Paolini

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 FcεRI-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 FcεRI-mediated cell degranulation. The purpose of this study was to further investigate whether CIN85 could alter the FcεRI-mediated signaling by affecting the activity and/or expression of molecules directly implicated in signal propagation. We found that CIN85 overexpression inhibits the FcεRI-induced tyrosine phosphorylation of phospholipase Cγ, 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.

Original languageEnglish
Pages (from-to)2089-2096
Number of pages8
JournalJournal of Immunology
Volume179
Issue number4
Publication statusPublished - Aug 15 2007

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Proteasome Endopeptidase Complex
Ubiquitin
Protein-Tyrosine Kinases
Proteins
Cell Degranulation
Ligases
Endocytosis
Receptor Aggregation
Syk Kinase
IgE Receptors
Proteasome Inhibitors
Basophils
Type C Phospholipases
Mast Cells
Immunoglobulin E
Tyrosine
Phosphorylation
Calcium

ASJC Scopus subject areas

  • Immunology

Cite this

Peruzzi, G., Molfetta, R., Gasparrini, F., Vian, L., Morrone, S., Piccoli, M., ... Paolini, R. (2007). The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. Journal of Immunology, 179(4), 2089-2096.

The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. / Peruzzi, Giovanna; Molfetta, Rosa; Gasparrini, Francesca; Vian, Laura; Morrone, Stefania; Piccoli, Mario; Frati, Luigi; Santoni, Angela; Paolini, Rossella.

In: Journal of Immunology, Vol. 179, No. 4, 15.08.2007, p. 2089-2096.

Research output: Contribution to journalArticle

Peruzzi, G, Molfetta, R, Gasparrini, F, Vian, L, Morrone, S, Piccoli, M, Frati, L, Santoni, A & Paolini, R 2007, 'The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway', Journal of Immunology, vol. 179, no. 4, pp. 2089-2096.
Peruzzi G, Molfetta R, Gasparrini F, Vian L, Morrone S, Piccoli M et al. The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. Journal of Immunology. 2007 Aug 15;179(4):2089-2096.
Peruzzi, Giovanna ; Molfetta, Rosa ; Gasparrini, Francesca ; Vian, Laura ; Morrone, Stefania ; Piccoli, Mario ; Frati, Luigi ; Santoni, Angela ; Paolini, Rossella. / The adaptor molecule CIN85 regulates syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. In: Journal of Immunology. 2007 ; Vol. 179, No. 4. pp. 2089-2096.
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