Vav family proteins constitute disparate branching points for distinct BCR signaling pathways.,European Journal of Immunology

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Vav family proteins constitute disparate branching points for distinct BCR signaling pathways.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-07-15 , DOI: 10.1002/eji.202048621
Jens Löber ₁ , Christoffer Hitzing ₁ , Matthias Münchhalfen ₁ , Niklas Engels ₁

Affiliation

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.

中文翻译：

Vav家族蛋白构成不同的BCR信号通路的不同分支点。

B细胞抗原受体（BCR）的抗原识别可激活不同的细胞内信号传导途径，从而控制活化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，磷酸酶和质膜脂质修饰酶，其功能进一步由催化惰性衔接蛋白调节。在这里，我们证明了Vav家族的鸟嘌呤核苷酸交换因子（GEF）提供的另一类酶促活性可控制BCR近端Ca ²⁺动员，细胞骨架肌动蛋白重组和PI3激酶/ Akt途径的激活。Vav1和Vav3在人类B细胞模型系统中以不同程度支持所有这些信号传导过程，而Vav2促进肌动蛋白重塑和Akt激活，但不促进Ca ²⁺信号传导。在BCR激活后，Vav1通过其Src同源2域直接募集到磷酸化的BCR和中央衔接蛋白SLP65。Vav GEFs底物的药理抑制或遗传失活，Rho / Rac家族的小G蛋白，损害了BCR诱导的Ca ²⁺动员，可能是因为磷脂酶Cγ2需要激活的Rac蛋白才能获得最佳活性。我们的发现表明，Vav家族成员是BCR信号小体的关键继电器，以催化依赖性和非依赖性方式差异控制不同的信号通路。

更新日期：2020-07-15

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