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Stimulation of beta1-integrin function by epidermal growth factor and heregulin-beta has distinct requirements for
M A Adelsman1, J B McCarthy, Y Shimizu
1Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Abstract:
Integrins and growth factor receptors are important participants in cellular adhesion and migration. The EGF receptor (EGFR) family of tyrosine kinases and the beta1-integrin adhesion receptors are of particular interest, given the implication for their involvement in the initiation and progression of tumorigenesis. We used adhesion and chemotaxis assays to further elucidate the relationship between these two families of transmembrane signaling molecules. Specifically, we examined integrin-mediated adhesive and migratory characteristics of the metastatic breast carcinoma cell line MDA-MB-435 in response to stimulation with growth factors that bind to and activate the EGFR or erbB3 in these cells. Although ligand engagement of the EGFR stimulated modest beta1-dependent increases in cell adhesion and motility, heregulin-beta (HRGbeta) binding to the erbB3 receptor initiated rapid and potent induction of breast carcinoma cell adhesion and migration and required dimerization of erbB3 with erbB2. Pharmacologic inhibitors of phosphoinositide 3-OH kinase (PI 3-K) or transient expression of dominant negative forms of PI 3-K inhibited both EGF- and HRGbeta-mediated adhesion and potently blocked HRGbeta- and EGF-induced cell motility. Our results illustrate the critical role of PI 3-K activity in signaling pathways initiated by the EGFR or erbB3 to up-regulate beta1-integrin function.
Insights
Heregulin-beta (HRGbeta) binding to erbB3 receptors potently induces breast cancer cell adhesion and migration, unlike EGF receptor (EGFR) activation. Phosphoinositide 3-OH kinase (PI 3-K) activity is critical for these beta1-integrin-mediated cellular responses.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Cancer Research
Background:
- Integrins and growth factor receptors, like the EGF receptor (EGFR) family, are crucial for cell adhesion and migration.
- Dysregulation of these pathways is implicated in tumorigenesis, particularly in breast cancer progression.
Purpose of the Study:
- To investigate the relationship between beta1-integrin and EGFR family signaling in breast carcinoma cell adhesion and migration.
- To elucidate the specific roles of EGFR and erbB3 receptor activation in mediating these cellular processes.
Main Methods:
- Adhesion and chemotaxis assays were performed on the MDA-MB-435 metastatic breast carcinoma cell line.
- Cells were stimulated with growth factors targeting EGFR and erbB3, and responses were analyzed with and without phosphoinositide 3-OH kinase (PI 3-K) inhibitors.
Main Results:
- Ligand engagement of EGFR induced modest beta1-integrin-dependent increases in adhesion and motility.
- Heregulin-beta (HRGbeta) binding to erbB3 triggered rapid, potent induction of cell adhesion and migration, dependent on erbB3/erbB2 dimerization.
- PI 3-K inhibition blocked both EGF- and HRGbeta-mediated adhesion and motility.
Conclusions:
- HRGbeta/erbB3 signaling, through erbB2 dimerization, is a potent regulator of beta1-integrin-mediated adhesion and migration in breast cancer cells.
- Phosphoinositide 3-OH kinase (PI 3-K) activity is essential for beta1-integrin functional regulation downstream of both EGFR and erbB3 signaling pathways.