Signal Transduction by Tissue Factor – An Unusual Cytokine Receptor

Abstract number: SYM03

Peppelenbosch¹ MP, Versteeg² HH, Borensztajn² K, Diks¹ S, Arnold Spek² C

¹¹Cell Biology, Groningen University Medical Center, Groningen, ••, The Netherlands ¹¹Cell Biology, Groningen University Medical Center, Groningen, ••, The Netherlands ²²Expermental Internal Medicine, Academic Medical Center, ••, the Netherlands

It is generally accepted that TF (tissue factor) Factor VIIa interaction provokes intracellular signal transduction in TF-expressing cells. The high homology between the extracellular part of TF and the proinflammatory interferon class II type receptors, especially the interferon receptor suggests that TF is a cytokine receptor, and we were able to show that VIIa activates the JAK/STAT signaling cassette, which is characteristic for this class of receptors. In silico analysis shows that all current members of the cytokine receptor class II family are derived from an ancient TF gene, as TF is the only member of the protein family found in teleosts. The functional significance of the intracellular domain of TF is under debate. To settle this issue we targeted full-length and intracellular mutant TF to specific loci in the genome (to avoid integration artifacts) and investigated VIIa-dependent signal transduction pathways by kinome profiling via peptide arrays containing substrates of all kinases in the mammalian genome. Preliminary results show that among the cellular signaling cascades targeted by TF are the MAP kinase pathway, the PI3 kinase pathway, Ca²⁺ signaling and activation of small GTPases. Further analysis of the data obtained should reveal the functionality of the intracellular domain.