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J. Cell Biol.,
Volume 144, Number 6, March 22, 1999 1337-1348
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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 (. J. Cell Sci.
109:631-642). We now demonstrate that the signal from
BM is mediated by integrins and requires both the 
6
and 
1 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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