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Volume 272, Number 34, Issue of August 22, 1997 pp. 21334-21340
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Critical Cytoplasmic Domains of Human Interleukin-9 Receptor  Chain in Interleukin-9-mediated Cell Proliferation and Signal Transduction

(Received for publication, December 9, 1996, and in revised form, June 13, 1997)

Yuan Xiao Zhu ^§ , Hui Bin Sun ^§ , Monica Lik-Shing Tsang ^¶ , Jon McMahel , Susan Grigsby , Tinggui Yin ^§ and Yu-Chung Yang ^§

From the Departments of  Medicine (Hematology/Oncology) and  Biochemistry and Molecular Biology, Indiana University School of Medicine and the ^§ Walther Cancer Institute, Indianapolis, Indiana 46202 and ^¶ R & D Systems, Minneapolis, Minnesota 55413-2647

Interleukin-9 receptor (IL-9R) complex consists of a ligand-specific  chain and IL-2R  chain. In this study, two regions in the cytoplasmic domain of human IL-9R were found to be important for IL-9-mediated cell growth. A membrane-proximal region that contains the BOX1 consensus sequence is required for IL-9-induced cell proliferation and tyrosine phosphorylation of Janus kinases (JAKs). Deletion of this region or internal deletion of the BOX1 motif abrogated IL-9-induced cell proliferation and signal transduction. However, substitution of the Pro-X-Pro in the BOX1 motif with Ala-X-Ala failed to abolish IL-9-induced cell proliferation but decreased IL-9-mediated tyrosine phosphorylation of JAK kinases, insulin receptor substrate-2, and signal transducer and activator of transcription 3 (STAT3) and expression of c-myc and junB. Another important region is downstream of the BOX1 motif and contains a STAT3 binding motif YLPQ. Deletion of this region significantly impaired IL-9-induced cell growth, activation of JAK kinases, insulin receptor substrate-2, and STAT3 and expression of early response genes. A point mutation changing YLPQ into YLPA greatly reduced IL-9-induced activation of STAT3 and expression of c-myc but did not affect cell proliferation. These results suggest that cooperation or cross-talk of signaling molecules associated with different domains of IL-9R other than STAT3 is essential for IL-9-mediated cell growth.

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