The Calponin Homology Domain of Vav1 Associates with Calmodulin and Is Prerequisite to T Cell Antigen Receptor-induced Calcium Release in Jurkat T Lymphocytes

• Published in: The Journal of biological chemistry 2007-08, Vol.282 (32), p.23737-23744
• Main Authors: Zhou, Zhuo, Yin, Jie, Dou, Zhixun, Tang, Jun, Zhang, Cuizhu, Cao, Youjia
• Format: Article
• Language: English
• Subjects: Calcium - metabolism; Calcium-Binding Proteins - chemistry; Calmodulin - chemistry; Calmodulin - metabolism; Calponins; Humans; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Jurkat Cells; Lymphocyte Activation; Microfilament Proteins - chemistry; Models, Biological; Phospholipase C gamma - metabolism; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-vav - chemistry; Proto-Oncogene Proteins c-vav - physiology; Receptors, Antigen, T-Cell - chemistry; T-Lymphocytes - metabolism; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M702975200

Vav1 is a guanine nucleotide exchange factor that is expressed specifically in hematopoietic cells and plays important roles in T cell development and activation. Vav1 consists of multiple structural domains so as to facilitate both its guanine nucleotide exchange activity and scaffold function following T cell antigen receptor (TCR) engagement. Previous studies demonstrated that the calponin homology (CH) domain of Vav1 is required for TCR-stimulated calcium mobilization and thus downstream activation of nuclear factor of activated T cells. However, it remained obscure how Vav1 functions in regulating calcium flux. In an effort to explore molecules interacting with Vav1, we found that calmodulin bound to Vav1 in a calcium-dependent and TCR activation-independent manner. The binding site was mapped to the CH domain of Vav1. Reconstitution of vav1-null Jurkat T cells (J.Vav1) with CH-deleted Vav1 exhibited a severe deficiency in calcium release to the same extent as that of Jurkat cells treated with the calmodulin inhibitor or J.Vav1 cells. The defect persisted even when phospholipase-Cγ1 was fully activated, indicating a prerequisite role of Vav1 CH domain in calcium signaling. The results suggest that Vav1 and calmodulin function cooperatively to potentiate TCR-induced calcium release. This study unveiled a mechanism by which the Vav1 CH domain is involved in calcium signaling and provides insight into our understanding of the role of Vav1 in T cell activation.