Tyk2 mediates effects of urokinase on human vascular smooth muscle cell growth.
The urokinase (uPA)/uPA receptor (uPAR) system plays a role in the response of the vessel wall to injury, presumably by modulating vascular smooth muscle cell (VSMC) functional behaviour. The Jak/Stat signaling pathway has been implicated to mediate the uPA/uPAR-directed cell migration and proliferation in VSMC. We have therefore investigated the underlying molecular mechanisms, which remained not completely understood. In particular, we aimed at identification of the kinase involved in the signaling cascade leading to Stat1 phosphorylation by uPA and its impact on VSMC growth. We performed expression in VSMC of kinase-deficient mutant forms of the Janus kinases Jak1 and Tyk2 and used different cell culture models imitating the response to vascular injury. We provide evidence that Tyk2, but not Jak1, mediates uPA-induced Stat1 phosphorylation and VSMC growth inhibition and suggest a novel function for Tyk2 as an important modulator of the uPA-directed VSMC functional behaviour at the place of injury.
Patecki
Margret
M
Medical Faculty of Charité, Franz Volhard Klinik, HELIOS Klinikum-Berlin, Max Delbrück Center, D-13125 Berlin, Germany.
von Schaewen
Markus
M
Tkachuk
Sergey
S
Jerke
Uwe
U
Dietz
Rainer
R
Dumler
Inna
I
Kusch
Angelika
A
D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D019000:Phosphotyrosine / Q000378:metabolism; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D019000:Phosphotyrosine; D053613:Janus Kinase 1; D053634:TYK2 Kinase; D014568:Urokinase-Type Plasminogen Activator