Specific Subdomains of Vav Differentially Affect T Cell and NK Cell Activation

摘要: The Vav protooncogene is a multidomain protein involved in the regulation of IL-2 gene transcription T cells and development cell-mediated killing by cytotoxic lymphocytes. We have investigated differential roles that specific subdomains within these two distinct cellular processes. Interestingly, calponin homology (CH) domain mutant (CH − ) fails to enhance NF-AT/AP-1-mediated but still able regulate killing. inability CH appears be secondary defective intracellular calcium, because 1) has significantly reduced TCR-initiated calcium signaling, 2) treatment with ionophore ionomycin or cotransfection activated calcineurin restores transcription. pleckstrin (PH) also been implicated regulating activation. found deletion PH yields can neither from NF-AT/AP-1 reporter nor TCR- FcR-mediated In contrast, natural cytotoxicity, indicating functional dichotomy for forms Lastly, mutation three tyrosines (Y142, Y160, Y174) acidic revealed potential negative regulatory site. Replacement all phenylalanine results hyperactive increases enhances cytotoxicity. Taken together, data highlight controlling functions. More broadly, suggest separate lymphocyte functions potentially modulated domain-specific targeting other critical signaling molecules.