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Journal of Biochemistry Advance Access published online on September 7, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm127
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© 2007 The Japanese Biochemical Society

Dok-1 is a positive regulator of IL-4 signaling and IgE response

Akane Inoue1,2, Tomoharu Yasuda1,2, Tadashi Yamamoto3 and Yuji Yamanashi1,*

1Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510. 3Division of Oncology, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639.

*To whom correspondence should be addressed: Prof. Yuji Yamanashi, Phone: +81-3-5803-5814, Fax: +81-3-5803-0241, E-mail: yamanashi.creg{at}mri.tmd.ac.jp

Received April 25, 2007; Accepted June 3, 2007


  Abstract

Interleukin-4 (IL-4) plays an essential role in the control of humoral immunity by regulating lymphocyte proliferation and differentiation, including the T helper type 2 lineage commitment of CD4+ T cells as well as the isotype switching to IgE in B cells. The adaptor protein Dok-1 is known to have an essential role in the negative regulation of a variety of cytokine signaling events. However, here we have found that the loss of Dok-1 impaired the proliferative response of CD4+ T cells and B cells to IL-4. Conversely, the forced expression of Dok-1 in the myeloid cell line 32D augmented the IL-4-induced proliferation, indicating a positive role for Dok-1. Tyrosine phosphorylation, and thereby the activation of Stat6 and IRS-2, is critical for IL-4 signaling; however, only the activation of Stat6, not the IRS-2-dependent phosphorylation of Akt, was perturbed in Dok-1-deficient cells stimulated with IL-4. Furthermore, mice lacking Dok-1 showed an impaired IgE response to thymus-dependent antigen. Thus, Dok-1 is a positive regulator of IL-4 signaling and IgE resonse.

Key Words: Dok, IgE, Interleukin-4, signal transduction, tyrosine phosphorylation

2These authors contributed equally to this work.


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