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Mol Cell Biol, February 1998, p. 742-752, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Definition of the Role of Tyrosine Residues of the Common beta  Subunit Regulating Multiple Signaling Pathways of Granulocyte-Macrophage Colony-Stimulating Factor Receptor

Tohru Itoh,1,2 Rui Liu,1 Takashi Yokota,2 Ken-ichi Arai,1 and Sumiko Watanabe1,*

Department of Molecular and Developmental Biology1 and Department of Stem Cell Regulation,2 The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108, Japan

Received 15 May 1997/Accepted 30 October 1997

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces various functions, including the proliferation and differentiation of a broad range of hematopoietic cells. We previously reported that at least two distinct pathways are involved in human GM-CSF receptor signaling; both require the box 1 region of the common beta  subunit (beta c). This region is essential for the activation of JAK2, which is necessary for all the biological functions of GM-CSF. The activation of JAK2 by GM-CSF leads to rapid tyrosine phosphorylation of cellular proteins, including the beta c. However, the significance of beta c phosphorylation with regard to the regulation of signaling molecules and the expression of GM-CSF functions is less well understood. Here we investigated the role of the cytoplasmic tyrosine residues of the beta c by using a series of beta c mutants expressed in murine BA/F3 cells. A mutant beta c with all eight cytoplasmic tyrosines converted to phenylalanine (Fall) activated JAK2 but not SHP-2, MAPK cascades, STAT5, or the c-fos promoter in BA/F3 cells, and it did not effectively induce proliferation. Adding back each tyrosine to Fall revealed that Tyr577, Tyr612, and Tyr695 are involved in the activation of SHP-2, MAPK cascades, and c-fos transcription, while every tyrosine, particularly Tyr612, Tyr695, Tyr750, and Tyr806, facilitated STAT5 activation. Impaired growth was also restored, at least partly, by any of the tyrosines. These results provide evidence that beta c tyrosines possess distinct yet overlapping functions in activating multiple signaling pathways induced by GM-CSF.

* Corresponding author. Mailing address: Department of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108, Japan. Phone: 81-3-5449-5660. Fax: 81-3-5449-5424. E-mail: sumiko{at}ims.u-tokyo.ac.jp.




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