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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.

Pubmed ID: 17675467

Authors

  • Peruzzi G
  • Molfetta R
  • Gasparrini F
  • Vian L
  • Morrone S
  • Piccoli M
  • Frati L
  • Santoni A
  • Paolini R

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

August 15, 2007

Associated Grants

None

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