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Journal of Biochemistry Advance Access published online on January 20, 2009
Journal of Biochemistry, doi:10.1093/jb/mvp013
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

The Influence of Domain Structures on The Signal Transduction of Chimeric Receptors Derived From the Erythropoietin Receptor

Wenhai Liu1, Masahiro Kawahara1,3,*, Hiroshi Ueda1,2,3 and Teruyuki Nagamune1,2,3

1Department of Chemistry and Biotechnology, School of Engineering, 2Department of Bioengineering, Graduate School of Engineering, and 3Center for NanoBio Integration (CNBI), The University of Tokyo, Tokyo, Japan

*To whom correspondence should be addressed: Masahiro Kawahara: Tel: +81-3-5841-7356; Fax: +81-3-5841-8657; E-mail: kawahara{at}bio.t.u-tokyo.ac.jp

Received December 8, 2008; Accepted January 10, 2009


  Abstract

Although cytokine receptors regulate many cellular functions, contribution of receptor's domains and their conformation to signal transduction remains unclear. In this study, we designed a series of chimeric erythropoietin receptor (EpoR) variants encoding a hemagglutinin epitope-tagged anti-fluorescein single-chain Fv and different combinations of extracellular D1/D2 domain(s) of EpoR as the extracellular domain to allow the receptor to be activated by multiple ligands. Furthermore, one to four Ala residues were inserted at the intracellular juxtamembrane region of each chimeric receptor to modulate the conformation of the intracellular domain. When the chimeric receptors were expressed in Ba/F3 cells, cell-surface expression levels of chimeric receptors without D2 domain were markedly lowered, suggesting a role of D2 domain for stabilizing the receptor. Furthermore, the ligand-dependent cell proliferation was strongly affected by extracellular domain structures and the number of inserted Ala residues. Moreover, the conformational change of chimeric receptors was induced by various ligands to detect the phosphorylation of JAK2, STAT5 and ERK2, whose activations are characteristics of EpoR signaling. Consequently, the phosphorylation pattern of these signal transducers was significantly influenced by ligands and receptor variants. These results indicate that signal transduction of EpoR is strongly affected by conformation of both extracellular and intracellular domains.

Key Words: chimeric receptor, conformational change, erythropoietin receptor, ligand, signal transduction


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