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Molecular and Cellular Biology, April 2000, p. 2734-2742, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Coupling of Osteopontin and Its Cell Surface Receptor CD44 to the Cell Survival Response Elicited by Interleukin-3 or Granulocyte-Macrophage Colony-Stimulating Factor

Yi-Hung Lin,1,2 Chang-Jen Huang,3 Jyh-Rong Chao,2 Shui-Tsung Chen,3 Shern-Fwu Lee,4 Jeffrey Jong-Young Yen,4 and Hsin-Fang Yang-Yen1,2,*

Graduate Institute of Life Science, National Defense Medical Center,1 and Institute of Molecular Biology,2 Institute of Biological Chemistry,3 and Institute of Biomedical Sciences,4 Academia Sinica, Taipei, Taiwan, Republic of China

Received 7 October 1999/Returned for modification 17 November 1999/Accepted 25 January 2000

The receptors for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) share a common beta  subunit, the distal cytoplasmic domain of which is essential for the promotion of cell survival by these two cytokines. Genes whose expression is specifically induced by signaling through the distal cytoplasmic domain of this receptor beta  subunit were screened by a subtraction cloning approach in derivatives of a mouse pro-B-cell line. One gene thus identified was shown to encode a protein highly homologous (with only 7 amino acid substitutions) to murine osteopontin (OPN), a secreted adhesion protein. Conditioned medium from cells expressing wild-type OPN, but not that from cells expressing a deletion mutant lacking residues 79 to 140, increased the viability of a non-OPN-producing cell line in the presence of human GM-CSF. Antibody blocking experiments revealed that OPN produced as a result of IL-3 or GM-CSF signaling was secreted into the medium and, through binding to its cell surface receptor, CD44, contributed to the survival-promoting activities of these two cytokines. Furthermore, coupling of the OPN-CD44 pathway to the survival response to IL-3 was also demonstrated in primary IL-3-dependent mouse bone marrow cells. These results thus show that induction of an extracellular adhesion protein and consequent activation of its cell surface receptor are important for the antiapoptotic activities of IL-3 and GM-CSF.

* Corresponding author. Mailing address: Institute of Molecular Biology, Academia Sinica, 128 Yen-Jiou Yuan Rd., Section 2, Nankang, Taipei 11529, Taiwan, Republic of China. Phone: 886-2-2789-9228. Fax: 886-2-2782-6085. E-mail: imbyy{at}ccvax.sinica.edu.tw.

Molecular and Cellular Biology, April 2000, p. 2734-2742, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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