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[Cancer Research 59, 5331-5340, October 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 5331-5340, October 15, 1999]
© 1999 American Association for Cancer Research

Tumor Biology

Biological Activities and Signaling Pathways of the Granulin/Epithelin Precursor1

Tommaso Zanocco-Marani, Andrew Bateman, Gaetano Romano, Barbara Valentinis, Zhi-Heng He and Renato Baserga2

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [T. Z-M., G. R., B. V., R. B.], and Endocrine Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1 Canada [A. B., Z-H. H.]

Growth-regulated cells, such as 3T3 mouse embryo fibroblasts (MEFs), require more than one growth factor for growth, usually the insulin-like growth factor I (IGF-I) in combination with either platelet-derived growth factor or epidermal growth factor. Singly, these growth factors cannot sustain the growth of 3T3 cells. However, if the IGF-I receptor (IGF-IR) is even modestly overexpressed, then IGF-I, by itself, stimulates the growth of MEFs in monolayer and makes them capable of forming colonies in soft agar. The granulin/epithelin precursor (GEP) has been identified as the only growth factor, thus far, that can stimulate by itself the growth of R- cells, a 3T3-like cell line in which the genes for the IGF-IR have been deleted. We have expressed GEP in R- cells and show that these cells can now grow in serum-free medium. GEP, however, cannot replace other functions of the IGF-IR, such as protection from apoptosis (anoikis) or transforming activity (colony formation in soft agar). GEP activates, in R- cells, the two signaling pathways that are known to be sufficient for IGF-I-mediated mitogenesis in cells overexpressing the IGF-IR, the mitogen-activated protein kinase and the phosphatidylinositol 3-kinase pathways. This may explain why GEP, by itself, can replace the IGF-IR for growth in monolayer cultures. It also confirms that, for transformation, other pathways must be activated besides the two pathways that are sufficient for mitogenesis.




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Copyright © 1999 by the American Association for Cancer Research.