Thrombin peptide, TP508, induces differential gene expression in fibroblasts through a nonproteolytic activation pathway

Exp Cell Res. 1999 Mar 15;247(2):422-31. doi: 10.1006/excr.1998.4372.


Prior studies have shown that synthetic peptides representing the domain of thrombin responsible for high-affinity binding to fibroblasts stimulate chemotactic and cell proliferative signals through a nonproteolytic mechanism. One of these peptides, TP508, has recently been shown to be chemotactic for neutrophils, to enhance collagen accumulation in wounds, to enhance revascularization of wounds, and to accelerate the healing of incisional and open wounds in normal animals and in animals with impaired healing. To determine whether TP508 activates the proteolytically activated receptor for thrombin (PAR1), or the signals that are activated by PAR1, we treated human fibroblasts with TP508 and the PAR1-activating peptide, SFLLRNP, and analyzed the effects of these peptides on gene expression using differential display reverse transcriptase polymerase chain reaction. TP508 induces expression of a number of specific message fragments with short tyrosine kinase-like domains that are not induced by SFLLRNP. Sequencing full-length clones prepared by Marathon extension of TP508-induced fragments revealed that among the induced transcripts, there was a sequence with 88% homology to human annexin V. Northern analysis with authentic annexin V cDNA confirms that TP508, but not SFLLRNP, induces expression of annexin V in human fibroblasts. These results demonstrate that TP508 activates a cellular response separate from that activated through PAR1 and supports the hypothesis that TP508 acts through a separate nonproteolytically activated thrombin receptor that may be responsible for high-affinity thrombin binding and for nonproteolytic signals that are required for thrombin stimulation of cell proliferation.

Publication types

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

MeSH terms

  • Annexin A5 / genetics
  • Blotting, Northern
  • DNA, Complementary
  • Fibroblasts
  • Gene Expression Regulation / drug effects*
  • Humans
  • Peptides / pharmacology*
  • Thrombin / pharmacology*


  • Annexin A5
  • DNA, Complementary
  • Peptides
  • Thrombin