期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：50
页码：21143-21148
DOI：10.1073/pnas.0911309106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Interleukin-2 tyrosine kinase (Itk) is a Tec family tyrosine kinase that mediates signaling processes after T cell receptor engagement. Activation of Itk requires recruitment to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. After activation, Itk phosphorylates and activates phospholipase C-{gamma}1 (PLC-{gamma}1), leading to production of two second messengers, DAG and IP3. We have previously shown that phosphorylation of PLC-{gamma}1 by Itk requires a direct, phosphotyrosine-independent interaction between the Src homology 2 (SH2) domain of PLC-{gamma}1 and the kinase domain of Itk. We now define this docking interface using a combination of mutagenesis and NMR spectroscopy and show that disruption of the Itk/PLC{gamma}1 docking interaction attenuates T cell signaling. The binding surface on PLC{gamma}1 that mediates recognition by Itk highlights a nonclassical binding activity of the well-studied SH2 domain providing further evidence that SH2 domains participate in important signaling interactions beyond recognition of phosphotyrosine.
关键词：substrate recognition ; T cell signaling ; Tec kinases
