CBAP promotes thymocyte negative selection by facilitating T-cell receptor proximal signaling

Abstract

T-cell receptor (TCR)-transduced signaling is critical to thymocyte development at the CD4/CD8 double-positive stage, but the molecules involved in this process are not yet fully characterized. We previously demonstrated that GM-CSF/IL-3/IL-5 receptor common β-chain-associated protein (CBAP) modulates ZAP70-mediated T-cell migration and adhesion. On the basis of the high expression of CBAP during thymocyte development, we investigated the function of CBAP in thymocyte development using a CBAP knockout mouse. CBAP-deficient mice showed normal early thymocyte development and positive selection. In contrast, several negative selection models (including TCR transgene, superantigen staphylococcal enterotoxin B, and anti-CD3 antibody treatment) revealed an attenuation of TCR-induced thymocyte deletion in CBAP knockout mice. This phenotype correlated with a reduced accumulation of BIM upon TCR crosslinking in CBAP-deficient thymocytes. Loss of CBAP led to reduced TCR-induced phosphorylation of proteins involved in both proximal and distal signaling events, including ZAP70, LAT, PLCγ1, and JNK1/2. Moreover, TCR-induced association of LAT signalosome components was reduced in CBAP-deficient thymocytes. Our data demonstrate that CBAP is a novel component in the TCR signaling pathway and modulates thymocyte apoptosis during negative selection.

CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell acute lymphoblastic leukemia

“…Our previous studies have reported the pro-apoptotic functions of CBAP in cytokine-dependent cell lines [22] or in primary hematopoietic cells [24, 25]. However, in the current study, we have discovered an important oncogenic and pro-proliferative role of CBAP in malignant hematological cells, such as T-ALL cells.…”

“…Previous studies have shown that CBAP is involved in ZAP70-dependent Vav1 phosphorylation and β1 integrin signalosome activation in chemokine-induced inside-out signaling [24]. It is also involved in LAT-PLCγ2-ZAP70 signalosome formation during TCR engagement [25]. We have previously mapped two discrete binding sites for Vav1 and Zap70 in the N-terminus of CBAP, as well as a β1 integrin binding site in the C-terminal half of the CBAP protein [24], but their functions remain unknown.…”

“…Quantitative reverse transcription PCR and cDNA synthesis were performed as described [25]. The primer sequences used for quantitative reverse transcription PCR of human CBAP were 5′-TGGCAAAGCTCTGTAGACCA-3′ (forward) and 5′-CTGGGCGGAACATAATGTGG-3′ (reverse).…”

“…Bioinformatics analyses have revealed that CBAP is a member of the Mab21 subfamily that lies within the nucleotide transferase protein fold superfamily [23]. Our previous studies have demonstrated that CBAP participates in chemokine-enhanced T-cell migration and adhesion [24] and in T-cell receptor engagement-induced phosphorylation of ZAP-70 and PLCγ1 [25]. Since CBAP proteins are highly expressed in many established tumor cell lines, including T-cell leukemia, we examined whether CBAP is also involved in leukemia proliferation and tumorigenesis.…”

Ovarian cancer risk score predicts chemo-response and outcome in epithelial ovarian carcinoma patients

“…The candidate genes for further survey included glypican-1 (GPC1) [ 14 ], cyclophilin B (CYPB) [ 15 ]. Mesothelin (MSLN) [ 16 ], LIM domain kinase 2 (LIMK2) [ 17 ], dedicator of cytokinesis 4 (DOCK4) [ 18 ], serine/threonine kinase 31 (STK31) [ 19 ], insulin-like growth factor-1 (IGF1) [ 20 ], chitinase 3-like 1 (CHI3L1) [ 21 ], survivin [ 22 23 24 25 ], and transmembrane protein 102 (TMEM102) of common beta-chain-associated protein (CBAP) [ 26 ].…”