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Molecular and Cellular Biology, May 1999, p. 3816-3828, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Insulin-Like Growth Factor I Synergizes with Interleukin 4 for Hematopoietic Cell Proliferation Independent of Insulin Receptor Substrate Expression

Lilian Soon,1 Lawrence Flechner,1 J. Silvio Gutkind,2 Lu-Hai Wang,3 Renato Baserga,4 Jacalyn H. Pierce,1 and Weiqun Li1,*

Laboratory of Cellular and Molecular Biology, National Cancer Institute,1 and Oral and Pharyngeal Cancer Branch, National Institute of Dental Research,2 Bethesda, Maryland 20892; Department of Microbiology, Mount Sinai School of Medicine, New York, New York 100293; and The Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 191074

Received 20 October 1998/Returned for modification 23 November 1998/Accepted 24 February 1999

In the present study, we investigated the potential role of insulin-like growth factor I (IGF-I) receptor (IGF-IR) in cell proliferation by overexpressing it in 32D myeloid progenitor cells. The overexpression of IGF-IR caused the transfectants to proliferate in response to IGF-I in the absence of insulin receptor substrate (IRS) expression. The activation of overexpressed wild-type IGF-IR, but not that of an ATP-binding mutant of IGF-IR, resulted in the increased tyrosine phosphorylation of several intracellular proteins, including SHC, Src homology 2-containing inositol-5-phosphatase, protein kinase C-delta , and Erk2. Grb2 association with SHC and mitogen-activated protein kinase (MAPK) activity was also enhanced in response to IGF-I stimulation. Interestingly, the stimulation of the IGF-IR transfectants with interleukin 4 (IL-4) also resulted in strong mitogenesis independent of IRS expression. Moreover, IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants. IL-4 was able to synergize with IGF-I for DNA synthesis, even in the parental 32D cells and a pro-B-cell line, Baf3, indicating the physiological importance of the two growth factors in hematopoietic cell proliferation. IL-4 stimulation of the IGF-IR transfectants resulted in enhanced tyrosine phosphorylation of SHC, Erk2, and signal transducer and activator of transcription 6 (STAT6) proteins. Both IL-4 and IGF-I were able to induce c-myc early response gene expression, and this expression was maximal in the presence of both factors. Finally, we demonstrated that a MAPK kinase inhibitor was able to suppress mitogenesis of the IGF-IR transfectants in response to IGF-I and/or IL-4. Together, our results suggest that IL-4 synergizes with IGF-I for hematopoietic cell proliferation, likely through cross talk between SHC/Grb2/MAPK and STAT6 pathways and through c-myc gene up-regulation.

* Corresponding author. Mailing address: Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bldg. 37, Room 1E24, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-1347. Fax: (301) 496-8479. E-mail: liwe{at}dc37a.nci.nih.gov.

Molecular and Cellular Biology, May 1999, p. 3816-3828, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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