Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
J Biol Chem. 2012 Jun 1;287(23):19725-35. doi: 10.1074/jbc.M111.309799. Epub 2012 Apr 3.
Robust elevation of the cytosolic calcium concentration is a crucial early step for T cell activation triggered by the T cell antigen receptor. Vav1 is a proto-oncogene expressed in hematopoietic cells that is indispensable for transducing the calcium-mobilizing signal. Following T cell receptor stimulation, Vav1 facilitates formation of signaling microclusters through multiple interactions with other proteins participating in the signaling cascade. Truncation of the N terminus of Vav1 produces its oncogenic version, which is unable to support normal calcium flux following T cell activation. We show here that truncation of the N-terminal region of Vav1 alters the fine structure of protein complexes in the signaling clusters, affecting the interaction of Vav1 with phospholipase Cγ1 (PLCγ1). This alteration is accompanied by a decrease in PLCγ1 phosphorylation and inhibition of inositol 1,4,5-trisphosphate production. We suggest that the structural integrity of the N-terminal region of Vav1 is important for the proper formation of the Vav1-associated signaling complexes. The oncogenic truncation of this region elicits conformational changes that interfere with the Vav1-mediated activation of PLCγ1 and that inhibit calcium mobilization.
细胞质钙离子浓度的稳定升高是 T 细胞受 T 细胞抗原受体激活的关键早期步骤。Vav1 是一种在造血细胞中表达的原癌基因，对于转导钙动员信号是不可或缺的。在 T 细胞受体刺激后，Vav1 通过与参与信号级联的其他蛋白质的多种相互作用，促进信号微簇的形成。Vav1 的 N 端截断产生其致癌形式，其在 T 细胞激活后无法支持正常的钙流。我们在这里表明，Vav1 的 N 端区域的截断改变了信号簇中蛋白质复合物的精细结构，影响了 Vav1 与磷脂酶 Cγ1（PLCγ1）的相互作用。这种改变伴随着 PLCγ1 磷酸化的减少和肌醇 1,4,5-三磷酸产生的抑制。我们认为，Vav1 N 端区域的结构完整性对于适当形成与 Vav1 相关的信号复合物是重要的。该区域的致癌截断引发构象变化，干扰 Vav1 介导的 PLCγ1 激活，并抑制钙动员。
