van Seventer G A, Mullen M M, van Seventer J M
Department of Pathology, University of Chicago, IL 60637-1463, USA.
Eur J Immunol. 1998 Nov;28(11):3867-77. doi: 10.1002/(SICI)1521-4141(199811)28:11<3867::AID-IMMU3867>3.0.CO;2-K.
Beta1 integrins can provide T cell co-stimulation, but little is known concerning their downstream signaling pathways. We found that Pyk2, a focal adhesion kinase-related tyrosine kinase, is regulated by beta1 integrin signaling in human T cells. Stimulation of Jurkat T cells with the alpha4beta1 integrin ligand VCAM-1 results in Pyk2 tyrosine phosphorylation, and combined stimulation with VCAM-1 and anti-CD3 mAb induces rapid and sustained synergistic Pyk2 phosphorylation. Studies with mAb suggest that in synergistic CD3- and alpha4beta1 integrin-mediated Pyk2 tyrosine phosphorylation, a major contribution of CD3-derived signals is independent of their effects on regulating integrin adhesion. Analysis of resting human CD4+ T cells confirmed the ability of CD3-derived signals to synergize with beta1 integrin-dependent signals in the induction of Pyk2 tyrosine phosphorylation. In addition, although CD28-mediated co-stimulatory signals were able to synergize with CD3-mediated signals in inducing ERK and JNK activation and secretion of IL-2 in the primary T cells, they did not contribute to the induction of Pyk2 phosphorylation. Taken together, these results indicate a potential role for Pyk2 in T cell co-stimulation mediated specifically by beta1 integrins.
β1整合素可提供T细胞共刺激，但对其下游信号通路却知之甚少。我们发现，粘着斑激酶相关酪氨酸激酶Pyk2在人T细胞中受β1整合素信号调控。用α4β1整合素配体VCAM-1刺激Jurkat T细胞会导致Pyk2酪氨酸磷酸化，而VCAM-1与抗CD3单克隆抗体的联合刺激则诱导快速且持续的协同性Pyk2磷酸化。单克隆抗体研究表明，在协同性CD3和α4β1整合素介导的Pyk2酪氨酸磷酸化过程中，CD3衍生信号的主要作用与其对调节整合素粘附的影响无关。对静息人CD4 + T细胞的分析证实，CD3衍生信号在诱导Pyk2酪氨酸磷酸化过程中能够与β1整合素依赖性信号协同作用。此外，虽然CD28介导的共刺激信号能够在原代T细胞中与CD3介导的信号协同作用诱导ERK和JNK活化以及IL-2分泌，但它们对Pyk2磷酸化的诱导并无作用。综上所述，这些结果表明Pyk2在由β1整合素特异性介导的T细胞共刺激中具有潜在作用。
