Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases.
Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases.
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DOI：
10.4049/jimmunol.155.10.4596
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发表时间：
1995-11
影响因子：
4.4
通讯作者：
S. Johnson;C. Pleiman;Lucy Y. Pao;J. Schneringer;K. Hippen;J. C. Cambier
中科院分区：
文献类型：
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作者：
S. Johnson;C. Pleiman;Lucy Y. Pao;J. Schneringer;K. Hippen;J. C. Cambier
T和B细胞Ag受体和某些IG Fc区受体（Fc γ RI、hFc γ RIIA、Fc γ RIII、Fc α R和Fc γ RI）的信号转导涉及保守序列基序，称为基于免疫受体酪氨酸的激活基序（ITAM），存在于多个受体链中。两个ITAM酪氨酸的磷酸化是信号转导中的关键事件。为了解决这种磷酸化的功能，我们评估了非磷酸化和双磷酸化（（p）2 ITAM）ITAM肽结合和修饰src和syk家族激酶在体内和体外的活性的能力。所有的（p）2 ITAM，但不是他们的非磷酸化的对应物，诱导广泛的蛋白质酪氨酸磷酸化透化细胞。然而，磷酸化的蛋白质的模式不同的（p）2 ITAM。发现这种磷酸化反应src家族激酶林恩的活化，而不是Syk。使用纯化的林恩进行的体外研究表明，src家族激酶活化是由与（p）2 ITAM的直接相互作用引起的。结合研究表明（p）2 ITAM的结合特异性存在明显差异。最引人注目的是，IG alpha（p）2 ITAM和TCR-zeta c以及CD 3 β（p）2 ITAM表现出对src和syk家族激酶的反向结合偏好。总而言之，这些发现证明了SRC家族酪氨酸激酶被激活的一种新机制，并且与以下可能性一致：由于不同的效应物Src同源2结构域（SH 2）结合偏好，不同的ITAM可能优先激活不同的信号传导途径。
Signal transduction by T and B cell Ag receptors and certain receptors for Ig Fc regions (Fc gamma RI, hFc gamma RIIA, Fc gamma RIII, Fc alpha R, and Fc epsilon RI) involves a conserved sequence motif, termed an immunoreceptor tyrosine-based activation motif (ITAM) and found in multiple receptor chains. Phosphorylation of the two ITAM tyrosines is a critical event in signal transduction. To address the function of this phosphorylation, we assessed the ability of nonphosphorylated and biphosphorylated ((p)2ITAM) ITAM peptides to bind and modify the activity of src and syk family kinases in vivo and in vitro. All (p)2ITAMs, but not their nonphosphorylated counterparts, induced extensive protein tyrosine phosphorylation in permeabilized cells. However, the patterns of proteins phosphorylated differed among (p)2ITAMs. This phosphorylation was found to reflect activation of the src family kinase Lyn, but not Syk. In vitro studies using purified Lyn showed that src family kinase activation resulted from a direct interaction with (p)2ITAM. Binding studies demonstrated clear differences in binding specificity of (p)2ITAMs. Most strikingly, Ig alpha (p)2ITAM and TCR-zeta c and CD3 epsilon (p)2ITAMs exhibit inverse binding preferences for src and syk family kinases. Taken together, these findings demonstrate a novel mechanism by which src family tyrosine kinases are activated, and are consistent with the possibility that different ITAMs may preferentially activate distinct signaling pathways as a consequence of distinct effector Src homology 2 domain (SH2) binding preference.