Serine phosphorylation of paxillin by heregulin-β1: Role of p38 mitogen activated protein kinase

Ratna Vadlamudi, Liana Adam, Amjad Talukder, John Mendelsohn, Rakesh Kumar

Research output: Contribution to journalArticle

64 Scopus citations

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 languageEnglish (US)
Pages (from-to)7253-7264
Number of pages12
JournalOncogene
Volume18
Issue number51
DOIs
StatePublished - Dec 2 1999
Externally publishedYes

Keywords

  • Heregulin
  • Motility
  • Paxillin
  • Signaling
  • Spreading

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Vadlamudi, R., Adam, L., Talukder, A., Mendelsohn, J., & Kumar, R. (1999). Serine phosphorylation of paxillin by heregulin-β1: Role of p38 mitogen activated protein kinase. Oncogene, 18(51), 7253-7264. https://doi.org/10.1038/sj.onc.1203163