A PLC-γ1 Feedback Pathway Regulates Lck Substrate Phosphorylation at the T-Cell Receptor and SLP-76 Complex,Journal of Proteome Research

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A PLC-γ1 Feedback Pathway Regulates Lck Substrate Phosphorylation at the T-Cell Receptor and SLP-76 Complex
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2017-07-06 00:00:00 , DOI: 10.1021/acs.jproteome.6b01026
Judson Belmont ₁ , Tao Gu ₁ , Ashley Mudd ₁ , Arthur R. Salomon _{1,

2}

Affiliation

Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T-cell signaling pathway. While its functions as a regulator of both Ca²⁺ signaling and PKC-family kinases are well characterized, PLC-γ1’s role in the regulation of early T-cell receptor signaling events is incompletely understood. Activation of the T-cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck. To determine if PLC-γ1 contributes to the regulation of these feedback networks, we performed a quantitative phosphoproteomic analysis of PLC-γ1-deficient T cells. These data revealed a previously unappreciated role for PLC-γ1 in the positive regulation of Zap-70 and T-cell receptor tyrosine phosphorylation. Conversely, PLC-γ1 negatively regulated the phosphorylation of SLP-76-associated proteins, including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr¹⁹² phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck’s targeting, but not its kinase activity, is altered by PLC-γ1, possibly through Lck Tyr¹⁹² phosphorylation and increased association of the kinase with protein scaffolds SLP-76 and TSAd.

中文翻译：

PLC-γ1反馈途径调节T细胞受体和SLP-76复合物上Lck底物的磷酸化

磷脂酶Cγ1（PLC-γ1）在T细胞信号传导途径中占有至关重要的位置。虽然它同时充当Ca ²⁺和Ca ²⁺的调节剂信号转导和PKC家族激酶已被很好地表征，PLC-γ1在早期T细胞受体信号转导事件调控中的作用尚不完全清楚。T细胞受体的激活导致SLP-76，LAT，PLC-γ1，Itk和Vav1之间形成信号体复合物。最近的研究揭示了从SLP-76到Lck途径中顶激酶的正反馈和负反馈途径均存在。为了确定PLC-γ1是否有助于调节这些反馈网络，我们对PLC-γ1缺陷型T细胞进行了磷酸化蛋白质组学定量分析。这些数据揭示了PLC-γ1在Zap-70和T细胞受体酪氨酸磷酸化正调控中的前所未有的作用。相反，PLC-γ1负调控SLP-76相关蛋白的磷酸化，包括先前在该复合物中建立的Lck底物磷酸化位点。虽然Lck上的正负调节磷酸化位点基本未变，但Tyr在Jgamma1中¹⁹²磷酸化升高。数据支持了一个模型，其中PLC-γ1可能通过Lck Tyr ¹⁹²磷酸化以及激酶与蛋白支架SLP-76和TSAd的缔合增加来改变Lck的靶向作用，但不改变其激酶活性。

更新日期：2017-07-12

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