Bottini Nunzio, Stefanini Lavinia, Williams Scott, Alonso Andres, Jascur Thomas, Abraham Robert T, Couture Clement, Mustelin Tomas
Program of Signal Transduction, La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
J Biol Chem. 2002 Jul 5;277(27):24220-4. doi: 10.1074/jbc.M202885200. Epub 2002 Apr 25.
The ZAP-70 protein-tyrosine kinase plays a central role in signaling from the T cell antigen receptor. Recruitment and activation of ZAP-70 are transient and are terminated by phosphorylation of negative regulatory tyrosine residues and dephosphorylation of positively acting sites. We report that the low molecular weight protein-tyrosine phosphatase (LMPTP) specifically dephosphorylates the negative regulatory Tyr-292 of ZAP-70, thereby counteracting inactivation of ZAP-70. Expression of low levels of LMPTP resulted in increased ZAP-70 phosphorylation, presumably at the activating Tyr-493 and other sites, increased kinase activity, and augmented downstream signaling to the mitogen-activated protein kinase pathway. The ZAP-70 Y292F mutant was not affected by LMPTP. Our results indicate that LMPTP, like CD45, dephosphorylates a negative regulatory tyrosine site in a protein-tyrosine kinase and thereby strengthens T cell receptor signaling.
ZAP-70蛋白酪氨酸激酶在T细胞抗原受体信号传导中起核心作用。ZAP-70的募集和激活是短暂的，并通过负调节酪氨酸残基的磷酸化和正性作用位点的去磷酸化而终止。我们报告称，低分子量蛋白酪氨酸磷酸酶（LMPTP）特异性地使ZAP-70的负调节酪氨酸-292去磷酸化，从而抵消ZAP-70的失活。低水平LMPTP的表达导致ZAP-70磷酸化增加，推测是在激活酪氨酸-493和其他位点，激酶活性增加，并增强了向丝裂原活化蛋白激酶途径的下游信号传导。ZAP-70 Y292F突变体不受LMPTP影响。我们的结果表明，LMPTP与CD45一样，使蛋白酪氨酸激酶中的负调节酪氨酸位点去磷酸化，从而增强T细胞受体信号传导。
