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TIMP-2 disrupts FGF-2-induced downstream signaling pathways

Dong-Wan Seo1, Soo Hyeon Kim, Seok-Hyun Eom

  • 1Department of Molecular Bioscience, Institute of Bioscience and Biotechnology, School of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea. dwseomb@kangwon.ac.kr

Microvascular Research
|August 30, 2008
PubMed

Insights

Tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits endothelial cell growth by binding to integrin alpha3beta1. This interaction suppresses fibroblast growth factor-2 (FGF-2) signaling pathways, including p42/44(MAPK) activation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Tissue inhibitor of metalloproteinases-2 (TIMP-2) is an endogenous inhibitor of matrix metalloproteinases.
  • TIMP-2 exhibits matrix metalloproteinase inhibition-independent activities that modulate angiogenic responses.
  • Previous research suggests TIMP-2 plays a role in regulating cell growth and signaling pathways.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TIMP-2 mediates growth inhibition in response to fibroblast growth factor-2 (FGF-2).
  • To elucidate the specific cell surface receptors and signaling molecules involved in TIMP-2's anti-proliferative effects.

Main Methods:

  • Utilized human microvascular endothelial cells.
  • Employed protein tyrosine phosphatase inhibitor (orthovanadate) and dominant-negative Shp-1 mutant to assess signaling pathways.
  • Investigated the role of integrin alpha3beta1 using blocking antibodies and siRNA-mediated gene silencing.
  • Measured p42/44(MAPK) activation and cell proliferation.

Main Results:

  • TIMP-2's inhibition of FGF-2 signaling was not dependent on protein tyrosine phosphatase activity.
  • TIMP-2 binding to integrin alpha3beta1 on endothelial cells was crucial for its inhibitory effects.
  • Disruption of integrin alpha3 or beta1 function abrogated TIMP-2's inhibition of FGF-2-induced p42/44(MAPK) activation and cell proliferation.
  • TIMP-2's effects were associated with Shp-1-dependent inhibition of p42/44(MAPK) signaling.

Conclusions:

  • TIMP-2 inhibits FGF-2-stimulated endothelial cell proliferation through a mechanism involving integrin alpha3beta1.
  • The interaction of TIMP-2 with integrin alpha3beta1 leads to Shp-1-dependent inhibition of p42/44(MAPK) signaling.
  • These findings reveal a novel MMP-independent pathway for TIMP-2 in regulating endothelial cell mitogenesis.

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