Vav family proteins constitute disparate branching points for distinct BCR signaling pathways
Vav family proteins constitute disparate branching points for distinct BCR signaling pathways
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DOI：
10.1002/eji.202048621
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发表时间：
2020-07
影响因子：
5.4
通讯作者：
Jens Löber;Christoffer Hitzing;Matthias Münchhalfen;N. Engels
中科院分区：
文献类型：
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作者：
Jens Löber;Christoffer Hitzing;Matthias Münchhalfen;N. Engels
B细胞抗原受体（BCRs）的抗原识别激活了不同的细胞内信号通路，控制了活化的B淋巴细胞的分化命运。BCR -近端信号转导酶包括蛋白酪氨酸激酶、磷酸酶和质膜脂修饰酶，其功能进一步由催化惰性适配蛋白协调。在这里，我们发现由Vav家族的鸟嘌呤-核苷酸交换因子（GEFs）提供的另一类酶活性控制BCR -近端Ca2+动员，细胞骨架肌动蛋白重组和pi3k /Akt通路的激活。在人B细胞模型系统中，Vav1和Vav3在不同程度上支持所有这些信号过程，而Vav2促进肌动蛋白重塑和Akt的激活，但不促进Ca2+信号传导。在BCR激活时，Vav1通过其Src同源2结构域直接被募集到磷酸化的BCR和中心接头蛋白SLP65上。药理抑制或基因失活Vav GEFs底物，Rho/Rac家族的小G蛋白，会损害BCR诱导的Ca2+动员，可能是因为磷脂酶Cγ2需要活化Rac蛋白才能达到最佳活性。我们的研究结果表明，Vav家族成员是BCR信号体的关键中继，以催化依赖性和非依赖性的方式不同地控制不同的信号通路。
Antigen recognition by B‐cell antigen receptors (BCRs) activates distinct intracellular signaling pathways that control the differentiation fate of activated B lymphocytes. BCR‐proximal signaling enzymes comprise protein tyrosine kinases, phosphatases, and plasma membrane lipid‐modifying enzymes, whose function is furthermore coordinated by catalytically inert adaptor proteins. Here, we show that an additional class of enzymatic activity provided by guanine‐nucleotide exchange factors (GEFs) of the Vav family controls BCR‐proximal Ca2+ mobilization, cytoskeletal actin reorganization, and activation of the PI3 kinase/Akt pathway. Whereas Vav1 and Vav3 supported all of those signaling processes to different extents in a human B‐cell model system, Vav2 facilitated Actin remodeling, and activation of Akt but did not promote Ca2+ signaling. On BCR activation, Vav1 was directly recruited to the phosphorylated BCR and to the central adaptor protein SLP65 via its Src homology 2 domain. Pharmacological inhibition or genetic inactivation of the substrates of Vav GEFs, small G proteins of the Rho/Rac family, impaired BCR‐induced Ca2+ mobilization, probably because phospholipase Cγ2 requires activated Rac proteins for optimal activity. Our findings show that Vav family members are key relays of the BCR signalosome that differentially control distinct signaling pathways both in a catalysis‐dependent and ‐independent manner.