Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-tyk2 interaction

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Item Type:	Article
Title:	Urokinase stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3-kinase-tyk2 interaction
Creators Name:	Kusch, A., Tkachuk, S., Haller, H., Dietz, R., Gulba, D.C., Lipp, M. and Dumler, I.
Abstract:	Janus kinases Jak1 and Tyk2 play an important role in urokinase-type plasminogen activator (uPA)-dependent signaling. We have recently demonstrated that both kinases are associated with the uPA receptor (uPAR) and mediate uPA-induced activation of signal transducers and activators of transcription (Stat1, Stat2, and Stat4) in human vascular smooth muscle cells (VSMC). Janus kinases are not only required for Stat activation but may also interfere with other intracellular signaling pathways. Here we report that in VSMC, Tyk2 interacts with a downstream signaling cascade involving phosphatidylinositol 3-kinase (PI3-K). We demonstrate that uPA induces PI3-K activation, which is abolished in VSMC expressing the dominant negative form of Tyk2. The regulatory subunit p85 of PI3-K co-immunoprecipitates with Tyk2 but not with Jak1, Jak2, or Jak3, and uPA stimulation increases the PI3-K activity in Tyk2 immunoprecipitates. Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion. We provide evidence that the Tyk2-mediated PI3-K activation in response to uPA is required for VSMC migration. Thus, two unrelated structurally distinct specific inhibitors of PI3-K, wortmannin and LY294002, prevent VSMC migration induced by uPA. No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2. Our results underscore the versatile function of Tyk2 in uPA-related intracellular signaling and indicate that PI3-K plays a selective role in the regulation of VSMC migration.
Keywords:	1-Phosphatidylinositol 3-Kinase, Androstadienes, Cell Movement, Chemotaxis, Chromones, Cultured Cells, Cytoskeleton, Dominant Genes, Enzyme Activation, Enzyme Inhibitors, Fluorescence Microscopy, Genetic Transcription, Glutathione Transferase, Morpholines, Northern Blotting, Precipitin Tests, Protein Binding, Protein-Tyrosine Kinases, Proteins, Recombinant Fusion Proteins, RNA, Signal Transduction, src Homology Domains, Time Factors, TYK2 Kinase, Tyrosine, Urinary Plasminogen Activator, Vascular Smooth Muscle, Video Microscopy
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	275
Number:	50
Page Range:	39466-39473
Date:	1 January 2000
PubMed:	View item in PubMed

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