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Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways

Ting Wang1, Kyoko Yamashita, Kazushi Iwata

  • 1Department of Biochemistry, School of Dentistry, Aichi-Gakuin University, 464-8650, Nagoya, Japan

Biochemical and Biophysical Research Communications
|July 31, 2002
PubMed

Insights

Tissue inhibitors of metalloproteinases (TIMPs) activate Ras, a key protein in cell growth. TIMP-1 uses the TYK/MAPK pathway, while TIMP-2 involves PKA signaling and PI3K interaction, revealing distinct mechanisms for TIMP-mediated cell proliferation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Oncology

Background:

  • Tissue inhibitors of metalloproteinases (TIMPs) exhibit growth-promoting effects on various cell types.
  • Ras proteins are critical regulators of cell proliferation, transformation, differentiation, and apoptosis.

Purpose of the Study:

  • To investigate the potential involvement of Ras in the cell growth-promoting activities of TIMP-1 and TIMP-2.
  • To elucidate the specific signaling pathways mediating Ras activation by TIMP-1 and TIMP-2.

Main Methods:

  • Utilized MG-63 human osteosarcoma cells to assess Ras activation.
  • Employed specific inhibitors: herbimycin A for tyrosine kinase (TYK) and H89 for protein kinase A (PKA).
  • Analyzed Ras-GTP levels and protein complex formation involving Ras-GTP and phosphoinositide 3-kinase (PI3K).

Main Results:

  • Both TIMP-1 and TIMP-2 dose-dependently increased Ras-GTP levels in MG-63 cells.
  • TIMP-1-induced Ras activation was dependent on the TYK/MAPK pathway, as shown by inhibition with herbimycin A.
  • TIMP-2-induced Ras activation involved the PKA pathway (inhibited by H89) and promoted Ras-GTP/PI3K complex formation.

Conclusions:

  • Ras signaling is a common mechanism underlying the growth-promoting effects of both TIMP-1 and TIMP-2.
  • TIMP-1 and TIMP-2 activate Ras through distinct signaling pathways: TYK/MAPK for TIMP-1 and PKA/PI3K for TIMP-2.
  • These findings highlight the complex roles of TIMPs in regulating cell growth and provide insights into potential therapeutic targets.

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