Direct Interaction of the CD38 Cytoplasmic Tail and the Lck SH2 Domain: CD38 TRANSDUCES T CELL ACTIVATION SIGNALS THROUGH ASSOCIATED Lck

Yee-Sook Cho,Myung-Kwan Han,Young Bong Choi,Yungdae Yun,Jaekyoon Shin,Uh-Hyun Kim

doi:10.1074/jbc.275.3.1685

Yee-Sook Cho, Myung-Kwan Han + Show 4 more

Open Access

https://doi.org/10.1074/jbc.275.3.1685

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Abstract

CD38 ligation has been shown to induce activation of intracellular signaling cascade in T lymphocytes through a Lck-dependent pathway. However, it is not clear how Lck initiates the CD38-mediated signaling process. In the present study, we showed that CD38 and Lck were physically associated through the cytoplasmic tail and the Src homology 2 domain, respectively. This was evidenced by coimmunoprecipitation of Lck with CD38 and Lck with isolated CD38 cytoplasmic domain from T cell lysate, cell lysate of COS-7 cells cotransfected with cDNAs of Lck and CD38, or a mixture of in vitro translated CD38 and Lck. Because the CD38 cytoplasmic domain does not contain any tyrosine residue, the interaction should be independent of phosphotyrosine. The interaction was further confirmed by in vitro interaction between a purified Lck Src homology 2 domain and a nonphosphosynthetic peptide corresponding to the membrane proximal region of the CD38 cytoplasmic domain. In addition, CD38 ligation resulted in an elevated tyrosine kinase activity of the CD38-associated Lck and ultimate activation of interleukin-2 gene transcription. Furthermore, expression of a kinase-deficient Lck mutant suppressed interleukin-2 gene activation in a dose-dependent manner. These results strongly suggested that CD38 ligation indeed tranduced signals for T cell activation using its associated Lck.

Highlights

CD38 ligation has been shown to induce activation of intracellular signaling cascade in T lymphocytes through a Lck-dependent pathway
It was shown that CD38 ligation induced Lck-regulated phosphorylation and/or activation of CD3␨, ZAP70, Ras-mitogen-activated protein kinase pathway, and other signaling molecules in Jurkat T cells [17]
The present study demonstrated that the cytoplasmic domain of CD38 directly associated with Lck via its SH2 domain (Figs. 1 and 2) and that ligation of CD38 up-regulates Lck tyrosine kinase, thereby inducing the ultimate activation of IL-2 gene transcription (Fig. 4)

Summary

Introduction

CD38 ligation has been shown to induce activation of intracellular signaling cascade in T lymphocytes through a Lck-dependent pathway. These results strongly suggested that CD38 ligation tranduced signals for T cell activation using its associated Lck. CD38 is a type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic tail [1].

Results

Conclusion