Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C

I N Fleming, C M Elliott, J G Collard, J H Exton

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Abstract

The Rho family of GTPases plays an important role in the control of cell shape, adhesion, movement, and growth. Several guanine nucleotide exchange factors have been identified that activate Rho family GTPases by promoting the binding of GTP to these proteins. However, little is known concerning the regulation of these GDP/GTP exchange factors. In this study, we demonstrate that lysophosphatidic acid (LPA) induces a rapid, sustainable phosphorylation of the Rac1-specific nucleotide exchange factor Tiam1 in Swiss 3T3 fibroblasts. LPA stimulated Tiam1 phosphorylation in a dose-dependent manner, and the protein was phosphorylated on threonine, but not tyrosine or serine. Tiam1 phosphorylation was also induced by platelet-derived growth factor, endothelin-1, bombesin, and bradykinin but not by epidermal growth factor. Significantly, pretreatment of Swiss 3T3 fibroblasts with 1 microM phorbol 12-myristate 13-acetate for 24 h, or with the selective protein kinase C inhibitor Ro-31-8220, reduced LPA-stimulated phosphorylation of Tiam1 by approximately 75%. Moreover, acute stimulation with 100 nM phorbol 12-myristate 13-acetate was sufficient to induce Tiam1 phosphorylation in vivo, and protein kinase C could phosphorylate purified Tiam1 on threonine residues in vitro. These data indicate that agonist-induced phosphorylation of Tiam1 is a general mechanism and suggest that it is likely to be important in its regulation. Protein kinase C appears to play a key role in phosphorylation of Tiam1.
Original languageEnglish
Pages (from-to)33105-10
Number of pages6
JournalThe Journal of Biological Chemistry
Volume272
Issue number52
Publication statusPublished - 1997

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Keywords

  • 3T3 Cells
  • Animals
  • Enzyme Activation
  • Fibroblasts
  • Guanine Nucleotide Exchange Factors
  • Lysophospholipids
  • Mice
  • Phosphorylation
  • Phosphothreonine
  • Protein Kinase C
  • Proteins
  • Tetradecanoylphorbol Acetate
  • Threonine

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