Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization.
Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization.
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DOI：
10.1084/jem.20060221
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发表时间：
2006-07-10
期刊：
影响因子：
--
通讯作者：
Nussenzweig MC
中科院分区：
文献类型：
--
作者：
Gazumyan A;Reichlin A;Nussenzweig MC
免疫球蛋白（IG）α和IGβ通过免疫受体酪氨酸激活基序（ITAM）启动B细胞受体（BCR）信号传导，ITAM是含SH 2结构域激酶的靶点。为了检测体内成熟B细胞中IGβ ITAM酪氨酸残基的功能，我们通过基因打靶（IGβAA）将这些残基换成丙氨酸。突变小鼠表现出所有B细胞亚型的正常发育，除了B1细胞减少了5倍。然而，从IGβAA小鼠纯化的原代B细胞显示出显著降低的稳态和配体介导的BCR内化以及较高水平的细胞表面IgM和IgD。BCR交联导致Src和Syk活化降低，但矛盾地增强和延长BCR信号传导，如通过细胞酪氨酸磷酸化、Ca++通量、AKT和ERK活化所测量的。此外，具有ITAM突变体受体的B细胞显示出对T非依赖性抗原的增强的应答。因此，IGβ ITAM酪氨酸通过调节受体内化来帮助设置BCR信号传导阈值。
Immunoglobulin (Ig)α and Igβ initiate B cell receptor (BCR) signaling through immune receptor tyrosine activation motifs (ITAMs) that are targets of SH2 domain–containing kinases. To examine the function of Igβ ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (IgβAA). Mutant mice showed normal development of all B cell subtypes with the exception of B1 cells that were reduced by fivefold. However, primary B cells purified from IgβAA mice showed significantly decreased steady-state and ligand-mediated BCR internalization and higher levels of cell surface IgM and IgD. BCR cross-linking resulted in decreased Src and Syk activation but paradoxically enhanced and prolonged BCR signaling, as measured by cellular tyrosine phosphorylation, Ca++ flux, AKT, and ERK activation. In addition, B cells with the ITAM mutant receptor showed an enhanced response to a T-independent antigen. Thus, Igβ ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.
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