Serine phosphorylation of paxillin by heregulin-beta1: role of p38 mitogen activated protein kinase

Oncogene. 1999 Dec 2;18(51):7253-64. doi: 10.1038/sj.onc.1203163.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Adhesion
  • Cell Adhesion Molecules / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Female
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neuregulin-1 / metabolism*
  • Paxillin
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Serine / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases


  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Neuregulin-1
  • PXN protein, human
  • Paxillin
  • Phosphoproteins
  • heregulin beta1
  • Serine
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases