Serine phosphorylation of paxillin by heregulin-beta1: role of p38 mitogen activated protein kinase.
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 non-invasive breast cancer cells resulted in stimulation of p38 mitogen-activated protein kinase (p38MAPK), 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 p38MAPK or a dominant-negative p38MAPK mutant, but not by inhibitors of p42/44MAPK 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 p38MAPK-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.
Vadlamudi
R
R
Cell Growth Regulation Laboratory, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Adam
L
L
Talukder
A
A
Mendelsohn
J
J
Kumar
R
R
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D020890:Neuregulin-1; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C087230:heregulin beta1; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases