Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2)

FEBS Lett. 1996 Oct 28;396(1):103-7. doi: 10.1016/0014-5793(96)01066-6.

Abstract

[3H]Thymidine (TdR) incorporation by human osteosarcoma cell line MG-63 was significantly stimulated at as early as 3 h after the addition of either TIMP-1 or TIMP-2 alone. Maximum stimulation was attained at a concentration of either 20 ng/ml (0.71 nM) TIMP-1 or 1.0 ng/ml (46 pM) TIMP-2. Tyrosine kinase inhibitors such as genistein, erbstatin, and herbimycin A almost completely inhibited the [3H]TdR incorporation stimulated by either of the TIMPs. However, essentially no effect was observed with H-89, H-7, bisindolylmaleimide and K-252a. These inhibition studies suggest a crucial role for tyrosine kinase in the signal transduction of TIMPs. Phosphotyrosine-containing proteins were significantly elevated by the treatment with both TIMPs. We also found that either TIMP stimulated an increase in mitogen-activated protein (MAP) kinase activity, suggesting that MAP kinase plays a role in TIMP-dependent growth signaling.

MeSH terms

  • Benzoquinones
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • DNA / biosynthesis
  • DNA / drug effects
  • Enzyme Activation
  • Genistein
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / metabolism*
  • Humans
  • Hydroquinones / metabolism
  • Hydroquinones / pharmacology
  • Isoflavones / metabolism
  • Isoflavones / pharmacology
  • Lactams, Macrocyclic
  • Mitogen-Activated Protein Kinase 1
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Phosphorylation
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / metabolism*
  • Quinones / metabolism
  • Quinones / pharmacology
  • Rifabutin / analogs & derivatives
  • Signal Transduction*
  • Thymidine / metabolism
  • Thymidine / pharmacokinetics
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-2
  • Tissue Inhibitor of Metalloproteinases
  • Tritium
  • Tumor Cells, Cultured
  • Tyrosine / metabolism*

Substances

  • Benzoquinones
  • Glycoproteins
  • Hydroquinones
  • Isoflavones
  • Lactams, Macrocyclic
  • Protease Inhibitors
  • Proteins
  • Quinones
  • Tissue Inhibitor of Metalloproteinases
  • Tritium
  • Tissue Inhibitor of Metalloproteinase-2
  • Rifabutin
  • Tyrosine
  • herbimycin
  • DNA
  • Genistein
  • Protein-Tyrosine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Thymidine
  • erbstatin