ROLE OF JANUS KINASE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTIONAND MITOGEN-ACTIVATED PROTEIN-KINASE CASCADES IN ANGIOTENSIN-II-INDUCED AND PLATELET-DERIVED GROWTH-FACTOR-INDUCED VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

In vascular smooth muscle cells, the induction of early growth respons e genes involves the janus kinase (JAK)/signal transducer and activato rs of transcription (STAT) and the Ras/Raf-1/mitogen-activated protein kinase cascades. In the present study, we found that electroporation of antibodies against MEH1 or ERK1 abolished vascular smooth muscle ce ll proliferation in response to either platelet-derived growth factor or angiotensin II, However, anti-STAT1 or -STAT3 antibody electroporat ion abolished proliferative responses only to angiotensin II and not t o platelet-derived growth factor, AG-490, a specific inhibitor of the JAK2 tyrosine kinase, prevented proliferation of vascular smooth muscl e cells, complex formation between JAK2 and Raf-1, the tyrosine phosph orylation of Raf-1, and the activation of ERK1 in response to either a ngiotensin II or platelet-derived growth factor. However AG-490 had no effect on angiotensin II- or platelet-derived growth factor-induced R as/Raf-1 complex formation, Our results indicate that: 1) STAT protein s play an essential role in angiotensin II-induced vascular smooth mus cle cell proliferation, 2) JAK2 plays an essential role in the tyrosin e phosphorylation of Raf-1, and 3) convergent mitogenic signaling casc ades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vasc ular smooth muscle cell proliferation in response to both growth facto r and G protein-coupled receptors.