Biological activities and signaling pathways of the granulin/epithelin precursor

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1999-10, Vol.59 (20), p.5331-5340
Main Authors: ZANOCCO-MARANI, T, BATEMAN, A, ROMANO, G, VALENTINIS, B, HE, Z.-H, BASERGA, R
Format: Article
Language:English
Subjects:
3T3 Cells
Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Animals
Apoptosis
Biological and medical sciences
Cell Division
Cell physiology
DNA - biosynthesis
Fundamental and applied biological sciences. Psychology
Growth Substances - genetics
Growth Substances - physiology
Mice
Mitogen-Activated Protein Kinases - physiology
Molecular and cellular biology
Protein-Serine-Threonine Kinases
Proteins - physiology
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins c-akt
Receptor, IGF Type 1 - physiology
RNA, Messenger - analysis
Shc Signaling Adaptor Proteins
Signal Transduction
Src Homology 2 Domain-Containing, Transforming Protein 1
Wound Healing
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Summary: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.
ISSN:0008-5472
1538-7445