Abstract
The growth-stimulating effects of thrombin are mediated primarily via activation of a G protein-coupled receptor, PAR-1. Because PAR-1 has no intrinsic tyrosine kinase activity, yet requires tyrosine phosphorylation events to induce mitogenesis, we investigated the role of the Janus tyrosine kinases (JAKs) in thrombin-mediated signaling. JAK2 was activated rapidly in rat vascular smooth muscle cells (VSMC) treated with thrombin, and signal transducers and activators of transcription (STAT1 and STAT3) were phosphorylated and translocated to the nucleus in a JAK2-dependent manner. AG-490, a JAK2-specific inhibitor, and a dominant negative JAK2 mutant inhibited thrombin-induced ERK2 activity and VSMC proliferation suggesting that JAK2 is upstream of the Ras/Raf/MEK/ERK pathway. To elucidate the functional significance of JAK-STAT activation, we studied the effect of thrombin on heat shock protein (Hsp) expression, based upon the following: 1) reports that thrombin stimulates reactive oxygen species production in VSMC; 2) the putative role of Hsps in modulating cellular responses to reactive oxygen species; and 3) the presence of functional STAT1/3-binding sites in Hsp70 and Hsp90beta promoters. Indeed, thrombin up-regulated Hsp70 and Hsp90 protein expression via enhanced binding of STATs to cognate binding sites in the Hsp70 and Hsp90 promoters. Together, these results suggest that JAK-STAT pathway activation is necessary for thrombin-induced VSMC growth and Hsp gene expression.
Highlights
PAR-1, angiotensin II (Ang II) receptor, and other G protein-coupled receptors, which do not themselves possess intrinsic tyrosine kinase activity, require tyrosine kinase activity to induce mitogenesis [8, 12,13,14]
Thrombin-induced Mitogenesis Is Inhibited by AG-490 —To understand the role of tyrosine phosphorylation in thrombininduced VSMC mitogenesis, we have investigated the effect of thrombin on the Janus kinases (JAKs)-signal transducers and activators of transcription (STATs) pathway
These results suggest that JAK2 plays a role in VSMC proliferation induced by the activation of G protein-coupled receptors and led us to test the activation of specific members of the JAKSTAT pathway in response to thrombin stimulation
Summary
PAR-1, angiotensin II (Ang II) receptor, and other G protein-coupled receptors, which do not themselves possess intrinsic tyrosine kinase activity, require tyrosine kinase activity to induce mitogenesis [8, 12,13,14]. These results suggest that JAK2 plays a role in VSMC proliferation induced by the activation of G protein-coupled receptors and led us to test the activation of specific members of the JAKSTAT pathway in response to thrombin stimulation.
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