综合的信号传导和转录组分析揭示了Src家族激酶的个体差异和其自身活性控制的新通路。
Integrated signaling and transcriptome analysis reveals Src family kinase individualities and novel pathways controlled by their constitutive activity.
发表日期：2023
作者：
Nikolaos Koutras, Vasileios Morfos, Kyriakos Konnaris, Adamantia Kouvela, Athanasios-Nasir Shaukat, Constantinos Stathopoulos, Vassiliki Stamatopoulou, Konstantina Nika
来源：
Frontiers in Immunology
摘要：
Src家族激酶（SFKs）Lck和Lyn对淋巴细胞的发育和功能至关重要。尽管它们的表达模式在组织限制方面存在差异，但这两种激酶共享相同的功能，其中最显著的是对抗原受体胞内尾部ITAM基序的磷酸化。Lck主要在T淋巴细胞中表达；然而，在B-1细胞亚群和包括急性和慢性B细胞白血病在内的许多病理情况中，它也可以在异位存在。Lck对B细胞信号传导装置的确切影响仍然不明确，并且引发了关于SFK成员之间选择性的机制的长期问题。在这项工作中，我们试图研究Lck在B细胞中异位功能的机制基础，并将其与主导的B细胞SFK Lyn引发的事件进行比较。我们的结果揭示了这两种SFKs显示的底物多样性，然而，这种多样性受到它们易感性差异的缓冲，揭示了SFK成员特异性微调方面迄今未被理解的一个方面。此外，我们展示了Lck和Lyn生成的信号足以在不存在受体/共受体结合的情况下诱导转录组变化，使其类似于B细胞激活。最后，我们的分析揭示了SFK在调节细胞应激反应平衡方面的尚未被认识的作用，促进了ER-噬菌体的开始，这是B淋巴细胞中一个完全未被表征的过程。版权所有 © 2023 Koutras, Morfos, Konnaris, Kouvela, Shaukat, Stathopoulos, Stamatopoulou and Nika.
The Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns the two kinases share common functions; the most pronounced one being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting question of mechanisms granting selectivity among SFK members. In this work we sought to investigate the mechanistic basis of ectopic Lck function in B-cells and compare it to events elicited by the predominant B-cell SFK, Lyn. Our results reveal substrate promiscuity displayed by the two SFKs, which however, is buffered by their differential susceptibility toward regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, we show that Lck- and Lyn-generated signals suffice to induce transcriptome alterations, reminiscent of B-cell activation, in the absence of receptor/co-receptor engagement. Finally, our analyses revealed a yet unrecognized role of SFKs in tipping the balance of cellular stress responses, by promoting the onset of ER-phagy, an as yet completely uncharacterized process in B lymphocytes.Copyright © 2023 Koutras, Morfos, Konnaris, Kouvela, Shaukat, Stathopoulos, Stamatopoulou and Nika.