Adherent epithelial cells require interactions with the extracellular matrix for their survival, though the mechanism is ill-defined. In long term cultures of primary mammary epithelial cells, a laminin-rich basement membrane (BM) but not collagen I suppresses apoptosis, indicating that adhesion survival signals are specific in their response (Pullan et al. 1996. J. Cell Sci. 109:631–642). We now demonstrate that the signal from BM is mediated by integrins and requires both the α6 and β1 subunits. In addition, a hormonal signal from insulin or insulin-like growth factors, but not hydrocortisone or prolactin, is necessary to suppress mammary cell apoptosis, indicating that BM and soluble factors cooperate in survival signaling. Insulin induced autophosphorylation of its receptor whether mammary cells were cultured on collagen I or BM substrata. However, both the tyrosine phosphorylation of insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase were enhanced in cells cultured on BM, as was the phosphorylation of the phosphatidylinositol 3-kinase effector, protein kinase B. These results suggest a novel extracellular matrix–dependent restriction point in insulin signaling in mammary epithelial cells. The proximal signal transduction event of insulin receptor phosphorylation is not dependent on extracellular matrix, but the activation of downstream effectors requires adhesion to BM. Since phosphatidylinositol 3-kinase was required for mammary epithelial cell survival, we propose that a possible mechanism for BM-mediated suppression of apoptosis is through its facilitative effects on insulin signaling.
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22 March 1999
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March 22 1999
Extracellular Matrix Regulates Apoptosis in Mammary Epithelium through a Control on Insulin Signaling
Nadia Farrelly,
Nadia Farrelly
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Yi-Ju Lee,
Yi-Ju Lee
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Janine Oliver,
Janine Oliver
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Caroline Dive,
Caroline Dive
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Charles H. Streuli
Charles H. Streuli
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Nadia Farrelly
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Yi-Ju Lee
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Janine Oliver
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Caroline Dive
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Charles H. Streuli
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
Address correspondence to Charles Streuli, School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK. Tel.: 44 161 275 5626. Fax: 44 161 275 7700. E-mail: [email protected]
C.H. Streuli is a Wellcome Senior Fellow in Basic Biomedical Science. C. Dive is a Lister Fellow.
Received:
March 13 1998
Revision Received:
February 10 1999
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1999
J Cell Biol (1999) 144 (6): 1337–1348.
Article history
Received:
March 13 1998
Revision Received:
February 10 1999
Citation
Nadia Farrelly, Yi-Ju Lee, Janine Oliver, Caroline Dive, Charles H. Streuli; Extracellular Matrix Regulates Apoptosis in Mammary Epithelium through a Control on Insulin Signaling . J Cell Biol 22 March 1999; 144 (6): 1337–1348. doi: https://doi.org/10.1083/jcb.144.6.1337
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