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) |
|---|---|
| Pages (from-to) | 7253-7264 |
| Number of pages | 12 |
| Journal | Oncogene |
| Volume | 18 |
| Issue number | 51 |
| State | Published - Dec 2 1999 |
| Externally published | Yes |
Fingerprint
Keywords
- Heregulin
- Motility
- Paxillin
- Signaling
- Spreading
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Serine phosphorylation of paxillin by heregulin-β1 : Role of p38 mitogen activated protein kinase. / Vadlamudi, Ratna K; Adam, Liana; Talukder, Amjad; Mendelsohn, John; Kumar, Rakesh.
In: Oncogene, Vol. 18, No. 51, 02.12.1999, p. 7253-7264.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Serine phosphorylation of paxillin by heregulin-β1
T2 - Role of p38 mitogen activated protein kinase
AU - Vadlamudi, Ratna K
AU - Adam, Liana
AU - Talukder, Amjad
AU - Mendelsohn, John
AU - Kumar, Rakesh
PY - 1999/12/2
Y1 - 1999/12/2
N2 - 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.
AB - 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.
KW - Heregulin
KW - Motility
KW - Paxillin
KW - Signaling
KW - Spreading
UR - http://www.scopus.com/inward/record.url?scp=0033518128&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033518128&partnerID=8YFLogxK
M3 - Article
C2 - 10602479
AN - SCOPUS:0033518128
VL - 18
SP - 7253
EP - 7264
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 51
ER -