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@ARTICLE{Rathnakumar:130388,
      author       = {K. Rathnakumar and S. Savant and H. Giri and A. Ghosh and
                      B. Fisslthaler and I. Fleming and U. Ram and A. K. Bera and
                      H. Augustin$^*$ and M. Dixit},
      title        = {{A}ngiopoietin-2 mediates thrombin-induced monocyte
                      adhesion and endothelial permeability.},
      journal      = {Journal of thrombosis and haemostasis},
      volume       = {14},
      number       = {8},
      issn         = {1538-7933},
      address      = {Oxford},
      publisher    = {Wiley-Blackwell},
      reportid     = {DKFZ-2017-05467},
      pages        = {1655 - 1667},
      year         = {2016},
      abstract     = {Essentials Mechanism of thrombin-induced inflammation is
                      not fully understood. Thrombin induced monocyte adhesion and
                      barrier loss require Angiopoietin-2 (Ang-2). Ang-2 mediates
                      vessel leakage and monocyte adhesion through SHP-2/p38MAPK
                      pathway. Calcium dependent SHP2/p38MAPK activation regulates
                      Ang-2 expression through a feedback loop.Background Thrombin
                      imparts an inflammatory phenotype to the endothelium by
                      promoting increased monocyte adhesion and vascular
                      permeability. However, the molecular players that govern
                      these events are incompletely understood. Objective The aim
                      of this study was to determine whether Angiopoietin-2
                      (Ang-2) has a role, if any, in regulating inflammatory
                      signals initiated by thrombin. Methods Assessment of
                      vascular leakage by Miles assay was performed by
                      intra-dermal injection on the foot paw. Surface levels of
                      intercellular adhesion molecule-1 (ICAM-1) were determined
                      by flow cytometry. Overexpression, knockdown and
                      phosphorylation of proteins were determined by Western
                      blotting. Results In time-course experiments,
                      thrombin-stimulated Ang-2 up-regulation, peaked prior to the
                      expression of adhesion molecule ICAM-1 in human umbilical
                      vein-derived endothelial cells (HUVECs). Knockdown of Ang-2
                      blocked both thrombin-induced monocyte adhesion and ICAM-1
                      expression. In addition, Ang-2(-/-) mice displayed defective
                      vascular leakage when treated with thrombin. Introducing
                      Ang-2 protein in Ang-2(-/-) mice failed to recover a
                      wild-type phenotype. Mechanistically, Ang-2 appears to
                      regulate the thrombin-activated calcium spike that is
                      required for tyrosine phosphatase SHP2 and p38 MAPK
                      activation. Further, down-regulation of SHP2 attenuated both
                      thrombin-induced Ang-2 expression and monocyte adhesion.
                      Down-regulation of the adaptor protein Gab1, a co-activator
                      of SHP2, as well as overexpression of the Gab1 mutant
                      incapable of interacting with SHP2 (YFGab1), inhibited
                      thrombin-mediated effects, including downstream activation
                      of p38 MAPK, which in turn was required for Ang-2
                      expression. Conclusions The data establish an essential role
                      of the Gab1/SHP2/p38MAPK signaling pathway and Ang-2 in
                      regulating thrombin-induced monocyte adhesion and vascular
                      leakage.},
      cin          = {A190},
      ddc          = {610},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {321 - Basic Concepts (POF3-321)},
      pid          = {G:(DE-HGF)POF3-321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27241812},
      doi          = {10.1111/jth.13376},
      url          = {https://inrepo02.dkfz.de/record/130388},
}