CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells.
The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl ... interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation- associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, B-Lymphocytes, Blotting, Western, Calcium, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cells, Cultured, Cyclin D2, Humans, Intracellular Signaling Peptides and Proteins, Lectins, C-Type, Microscopy, Fluorescence, NFATC Transcription Factors, Phospholipase C gamma, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-vav, RNA Interference, Receptors, Antigen, B-Cell, Signal Transduction, Ubiquitination, bcl-X Protein
Adaptor Proteins, Signal Transducing, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, B-Lymphocytes, Blotting, Western, Calcium, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cells, Cultured, Cyclin D2, Humans, Intracellular Signaling Peptides and Proteins, Lectins, C-Type, Microscopy, Fluorescence, NFATC Transcription Factors, Phospholipase C gamma, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-vav, RNA Interference, Receptors, Antigen, B-Cell, Signal Transduction, Ubiquitination, bcl-X Protein
Blood
Date: Mar. 08, 2012
PubMed ID: 22262777
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