title: Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling.
abstract: Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Felcht
authors.forename: Robert
authors.initials: R
authors.lastname: Luck
authors.forename: Alexander
authors.initials: A
authors.lastname: Schering
authors.forename: Philipp
authors.initials: P
authors.lastname: Seidel
authors.forename: Kshitij
authors.initials: K
authors.lastname: Srivastava
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.forename: Arne
authors.initials: A
authors.lastname: Bartol
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kienast
authors.forename: Christiane
authors.initials: C
authors.lastname: Vettel
authors.forename: Elias K
authors.initials: EK
authors.lastname: Loos
authors.forename: Simone
authors.initials: S
authors.lastname: Kutschera
authors.forename: Susanne
authors.initials: S
authors.lastname: Bartels
authors.forename: Sila
authors.initials: S
authors.lastname: Appak
authors.forename: Eva
authors.initials: E
authors.lastname: Besemfelder
authors.forename: Dorothee
authors.initials: D
authors.lastname: Terhardt
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Chavakis
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Markus
authors.initials: M
authors.lastname: Thomas
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Uemura
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D016023:Integrins; D009363:Neoplasm Proteins; D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein