Article

Angiopoietin-2 Stimulation of Endothelial Cells Induces v 3 Integrin Internalization and Degradation

Joint Research Division Vascular Biology, Medical Faculty Mannheim (CBTM), Heidelberg University, D-69120 Heidelberg, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2010; 285(31):23842-9. DOI: 10.1074/jbc.M109.097543
Source: PubMed

ABSTRACT The angiopoietins (Ang-1 and Ang-2) have been identified as agonistic and antagonistic ligands of the endothelial receptor tyrosine kinase Tie2, respectively. Both ligands have been demonstrated to induce translocation of Tie2 to cell-cell junctions. However, only Ang-1 induces Tie2-dependent Akt activation and subsequent survival signaling and endothelial quiescence. Ang-2 interferes negatively with Ang-1/Tie2 signaling, thereby antagonizing the Ang-1/Tie2 axis. Here, we show that both Ang-1 and Ang-2 recruit beta3 integrins to Tie2. This co-localization is most prominent in cell-cell junctions. However, only Ang-2 stimulation resulted in complex formation among Tie2, alphavbeta3 integrin, and focal adhesion kinase as evidenced by co-immunoprecipitation experiments. Focal adhesion kinase was phosphorylated in the FAT domain at Ser(910) upon Ang-2 stimulation and the adaptor proteins p130Cas and talin dissociated from alphavbeta3 integrin. The alphavbeta3 integrin was internalized, ubiquitinylated, and gated toward lysosomes. Taken together, the experiments define Tie2/alphavbeta3 integrin association-induced integrin internalization and degradation as mechanistic consequences of endothelial Ang-2 stimulation.

0 Followers
 · 
101 Views
  • Source
    • "with subsequent integrin internalization and degradation [20]. We and others have shown that Ang-2 levels in plasma from critically-ill septic patients correlate with the extent of pulmonary vascular leak and acute lung injury [21] [22], increase with the severity of multiple-organ dysfunction syndrome [23] [24], and independently predict mortality in the intensive care unit (ICU) [23] [24] [25] [26] [27] [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome.
    Cytokine 07/2012; 60(2):352-9. DOI:10.1016/j.cyto.2012.04.002 · 2.87 Impact Factor
  • Source
    • "However, it was not determined if α v β 3 integrin was ubiquitylated at the cell surface, resulting in receptor internalization or if ubiquitylation occurred post internalization. Additionally, α v β 3 integrin colocalized with the lysosome marker LAMP1 after 1 hour of angiopoietin-2 treatment, but whether α v β 3 integrin trafficking to lysosomes required ubiquitylation was not determined (Thomas et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenovirus relies on numerous interactions between viral and host cell proteins to efficiently enter cells. Undoubtedly, post-translational modifications of host and cellular proteins can impact the efficiency of this cell entry process. Ubiquitylation, once simply thought of as a modification targeting proteins for proteasomal degradation, is now known to regulate protein trafficking within cells, protein-protein interactions and cell signalling pathways. Accumulating evidence suggests that protein ubiquitylation can influence all stages of the life cycle of other viruses such as cell entry, replication and egress. Until recently, the influence of ubiquitylation has only been documented during adenovirus replication. This review highlights the most recent evidence demonstrating direct engagement of host ubiquitylation and SUMOylation machinery by adenovirus during cell entry. Additionally, potential roles for host protein ubiquitylation and the potential for adenovirus regulation of host ubiquitylation machinery during cell entry are discussed.
    Biology of the Cell 03/2012; 104(3):188-98. DOI:10.1111/boc.201100096 · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. A poorly understood clinical manifestation of pathological angiogenesis is angiodysplasia, vascular malformations that cause severe gastrointestinal bleeding. Angiodysplasia can be associated with von Willebrand disease (VWD), the most common bleeding disorder in man. VWD is caused by a defect or deficiency in von Willebrand factor (VWF), a glycoprotein essential for normal hemostasis that is involved in inflammation. We hypothesized that VWF regulates angiogenesis. Inhibition of VWF expression by short interfering RNA (siRNA) in endothelial cells (ECs) caused increased in vitro angiogenesis and increased vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)-dependent proliferation and migration, coupled to decreased integrin αvβ3 levels and increased angiopoietin (Ang)-2 release. ECs expanded from blood-derived endothelial progenitor cells of VWD patients confirmed these results. Finally, 2 different approaches, in situ and in vivo, showed increased vascularization in VWF-deficient mice. We therefore identify a new function of VWF in ECs, which confirms VWF as a protein with multiple vascular roles and defines a novel link between hemostasis and angiogenesis. These results may have important consequences for the management of VWD, with potential therapeutic implications for vascular diseases.
    Blood 11/2010; 117(3):1071-80. DOI:10.1182/blood-2010-01-264507 · 10.43 Impact Factor
Show more