title: CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells.
abstract: 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.
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. hniiro@med.kyushu-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Siamak
authors.initials: S
authors.lastname: Jabbarzadeh-Tabrizi
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shima
authors.forename: Kumiko
authors.initials: K
authors.lastname: Noda
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Ota
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tsuzuki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Eishi
authors.initials: E
authors.lastname: Baba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Takahiko
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Taniyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008856:Microscopy, Fluorescence; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D054875:Ubiquitination; D051020:bcl-X Protein / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D056742:Cyclin D2; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D050778:NFATC Transcription Factors; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases; D050721:Proto-Oncogene Proteins c-cbl; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; D000072377:Syk Kinase; D051020:bcl-X Protein; D000099192:CD69 Antigens; C113939:B cell linker protein; C494811:BCL2L1 protein, human; C433810:SH3KBP1 protein, human; C093651:VAV2 protein, human; C000606896:SYK protein, human; C067419:CBL protein, human