Inactivation of mitogen-activated protein kinases by a mammalian tyrosine-specific phosphatase, PTPBR7

Biochem Biophys Res Commun. 1999 Mar 5;256(1):52-6. doi: 10.1006/bbrc.1999.0278.

Abstract

Mitogen-activated protein kinase (MAPK) is inactivated through dephosphorylation of tyrosyl and threonyl regulatory sites. In yeast, both dual-specificity and tyrosine-specific phosphatases are involved in dephosphorylation. In mammals, however, no tyrosine-specific phosphatase has been identified molecularly to dephosphorylate MAPK in vivo. Recently, we and others have cloned a murine tyrosine-specific phosphatase, PTPBR7/PTP-SL, which is expressed predominantly in the brain. Here we report inactivation of the extracellular signal-regulated kinase (ERK) family MAPK by PTPBR7. PTPBR7 made complexes with ERK1/ERK2 in vivo and dephosphorylated ERK1 in vitro. When overexpressed in mammalian cells, wild-type PTPBR7 suppressed the phosphorylation and activation of ERK by epidermal growth factor (EGF), nerve growth factor (NGF), and constitutively active MEK1, a mutant MAPK kinase. In contrast, catalytically inactive and ERK-binding-deficient mutants revealed little inhibition on the ERK cascade. These results indicate that PTPBR7 suppresses MAPK directly in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Catalytic Domain / genetics
  • Cell Line
  • Cell Membrane / enzymology
  • Cytosol / enzymology
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases*
  • Mutation
  • Nerve Growth Factors / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • PC12 Cells
  • Phosphorylation / drug effects
  • Precipitin Tests
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Receptor-Like Protein Tyrosine Phosphatases, Class 7
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Yeasts / genetics
  • Yeasts / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • Epidermal Growth Factor
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • PTPRR protein, human
  • Protein Tyrosine Phosphatases
  • Ptprr protein, rat
  • Receptor-Like Protein Tyrosine Phosphatases, Class 7