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Molecular and Cellular Biology, October 2000, p. 7132-7139, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Coiled-Coil Domain of Stat3 Is Essential for Its SH2 Domain-Mediated Receptor Binding and Subsequent Activation Induced by Epidermal Growth Factor and Interleukin-6

Tong Zhang, Wei Hua Kee, Kah Tong Seow, Winnie Fung,dagger and Xinmin Cao*

Institute of Molecular and Cell Biology, Singapore 117609, Singapore

Received 7 March 2000/Returned for modification 19 April 2000/Accepted 20 June 2000

STAT proteins are a family of latent transcription factors that mediate the response to various cytokines and growth factors. Upon stimulation by cytokines, STAT proteins are recruited to the receptors via their SH2 domains, phosphorylated on a specific tyrosine, dimerized, and translocated into the nucleus, where they bind specific DNA sequences and activate the target gene transcription. STATs share highly conserved structures, including an N-domain, a coiled-coil domain, a DNA-binding domain, a linker domain, and an SH2 domain. To investigate the role of the coiled-coil domain, we performed a systematic deletion analysis of the N-domain and each of the alpha -helices and mutagenesis of conserved residues in the coiled-coil region of Stat3. Our results indicate that the coiled-coil domain is essential for Stat3 recruitment to the receptor and the subsequent tyrosine phosphorylation and tyrosine phosphorylation-dependent activities, such as dimer formation, nuclear translocation, and DNA binding, stimulated by epidermal growth factor (EGF) or interleukin-6 (IL-6). Single mutation of Asp170 or, to a lesser extent, Lys177 in alpha -helix 1 diminishes both receptor binding and tyrosine phosphorylation. Furthermore, the Asp170 mutant retains its ability to bind to DNA when phosphorylated on Tyr705 by Src kinase in vitro, implying a functional SH2 domain. Finally, we demonstrate a direct binding of Stat3 to the receptor. Taken together, our data reveal a novel role for the coiled-coil domain that regulates the early events in Stat3 activation and function.

* Corresponding author. Mailing address: Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore. Phone: (65) 874-3795. Fax: (65) 779-1117. E-mail: mcbcaoxm{at}imcb.nus.edu.sg.

dagger Present address: Marine Biotechnology Laboratory, Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.

Molecular and Cellular Biology, October 2000, p. 7132-7139, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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