Abstract
The mechanisms through which heregulin (HRG) regulates the progression of breast cancer cells to a more invasive phenotype are currently unknown. Recently we have shown that HRG treatment of breast cancer cells leads to the formation of lamellipodia/filopodia, and increased cell migration and invasiveness through the phosphatidylinositol 3-kinase (PI-3 kinase). Since the process of cell migration must involve changes in adhesion, we explored the potential HRG regulation of paxillin, a major cytoskeletal phosphoprotein of focal adhesion. We report that HRG stimulation of noninvasive breast cancer cells resulted in stimulation of p38 mitogen-activated protein kinase (p38(MAPK)), extracellular signal-regulated kinases (ERK) and PI-3K, and a concurrent unexpected increase in the level of paxillin phosphorylation on serine residue which was sensitive to protein-phosphatase 2b but not to protein tyrosine phosphatase 1. In addition, HRG triggered a rapid redistribution of paxillin to the perinuclear regions from the tyrosine-phosphorylated focal adhesions. and increased cell scattering. There was no effect of HRG on the state of phosphorylation and localization of focal adhesion kinase. The HRG-induced increase in serine phosphorylation of paxillin and cell scattering were selectively inhibited by a specific inhibitor of p38(MAPK) or a dominant-negative p38(MAPK) mutant, but not by inhibitors of p42/44(MAPK) or PI-3 kinase pathways. For the first time our results have shown that HRG, a potent migratory growth factor stimulates serine phosphorylation of paxillin. These findings suggest a role of p38(MAPK)-dependent signal transduction pathway(s) in serine phosphorylation and disassembly of the paxillin from the focal complexes during HRG-induced cell shape alterations and motility.
Original language | English (US) |
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Pages (from-to) | 7253-7264 |
Number of pages | 12 |
Journal | Oncogene |
Volume | 18 |
Issue number | 51 |
DOIs | |
State | Published - Dec 2 1999 |
Externally published | Yes |
Keywords
- Heregulin
- Motility
- Paxillin
- Signaling
- Spreading
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research