TIMP-2 growth-stimulatory activity: a concentration- and cell type-specific response in the presence of insulin

Exp Cell Res. 1996 Apr 10;224(1):110-5. doi: 10.1006/excr.1996.0117.


In addition to proteinase-inhibitory activities, growth-stimulatory activities have been described for all three known members of the tissue inhibitors of the metalloproteinase (TIMP) family, TIMP-1, TIMP-2, and ChIMP-3, believed to be the chicken homologue of TIMP-3. However, the mechanism by which the TIMPs stimulate cell growth is unclear. In this report we have demonstrated that rTIMP-2 was growth-stimulatory for human foreskin fibroblasts (HSF4, HSF43, HS68), lung adenocarcinoma cells (A549), human melanoma cells (WM115), and the Burkitt's lymphoma cell line RAMOS, and this stimulatory response was concentration-dependent, with the greatest stimulation occurring a 10-30 pM rTIMP-2 in [3H]thymidine incorporation assays and at 20-100 pM in cell growth assays. Normal human colon (18Co) and lung (37Lu) fibroblasts showed no response to rTIMP-2. [3H]Thymidine incorporation was inhibited by rTIMP-2 treatment in the nonadherent cell line HL60. These studies also demonstrated that for the cell types tested, TIMP-2 alone was insufficient for a growth stimulatory response requiring, at a minimum, the presence of insulin. In the absence of any "co-factor(s)," such as insulin, TIMP-2 treatment was inhibitory.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Humans
  • Insulin / pharmacology*
  • Protease Inhibitors / pharmacology*
  • Proteins / pharmacology*
  • Recombinant Proteins / pharmacology
  • Tissue Inhibitor of Metalloproteinase-2


  • Insulin
  • Protease Inhibitors
  • Proteins
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-2