title: Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells.
abstract: Angiogenesis is tightly regulated through complex crosstalk between pro- and anti-angiogenic signals. High molecular weight kininogen (HK) is an endogenous protein that is proteolytically cleaved in plasma and on endothelial cell surfaces to HKa, an anti-angiogenic protein. Ferritin binds to HKa and blocks its anti-angiogenic activity. Here, we explore mechanisms underlying the cytoprotective effect of ferritin in endothelial cells exposed to HKa. We observe that ferritin promotes adhesion and survival of HKa-treated cells and restores key survival and adhesion signaling pathways mediated by Erk, Akt, FAK and paxillin. We further elucidate structural motifs of both HKa and ferritin that are required for effects on endothelial cells. We identify an histidine-glycine-lysine (HGK) -rich antiproliferative region within domain 5 of HK as the target of ferritin, and demonstrate that both ferritin subunits of the H and L type regulate HKa activity. We further demonstrate that ferritin reduces binding of HKa to endothelial cells and restores the association of uPAR with α5β1 integrin. We propose that ferritin blocks the anti-angiogenic activity of HKa by reducing binding of HKa to UPAR and interfering with anti-adhesive and anti-proliferative signaling of HKa.
authors: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors: Lia
authors: L
authors: Tesfay
authors: Annissa J
authors: AJ
authors: Huhn
authors: Heather
authors: H
authors: Hatcher
authors: Frank M
authors: FM
authors: Torti
authors: Suzy V
authors: SV
authors: Torti
mesh_terms: D020816:Amino Acid Motifs; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005293:Ferritins / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051419:Paxillin / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D039081:Integrin alpha5beta1; D019679:Kininogen, High-Molecular-Weight; D051419:Paxillin; D005293:Ferritins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt