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All rights reserved. http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#_6 http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/version 20131211 http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#_5 http://www.w3.org/ns/prov#value 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. http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#_5 http://www.w3.org/ns/prov#wasQuotedFrom http://www.ncbi.nlm.nih.gov/pubmed/11278437 http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#_6 http://www.w3.org/2000/01/rdf-schema#label Selventa http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#assertion http://www.w3.org/ns/prov#hadPrimarySource http://www.ncbi.nlm.nih.gov/pubmed/11278437 http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#assertion http://www.w3.org/ns/prov#wasDerivedFrom http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#_5 http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI#pubinfo http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI http://purl.org/dc/terms/created 2014-07-03T14:31:40.552+02:00 http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI http://purl.org/pav/createdBy http://orcid.org/0000-0001-6818-334X http://www.tkuhn.ch/bel2nanopub/RAu0iCvd3yMb7jkdfl4ZtalZn7BMPFQdgaUS_0sW5LiAI http://purl.org/pav/createdBy http://orcid.org/0000-0002-1267-0234