Angiogenin activates Erk1/2 in human umbilical vein endothelial cells

Angiogenin is a potent angiogenic factor that binds to endothelial cells an d is endocytosed and rapidly translocated to the nucleus where it is concen trated in the nucleolus and binds to DNA. Angiogenin also activates cell-as sociated proteases, induces cell invasion and migration, stimulates cell pr oliferation, and organizes cultured cells to form tubular structures. The i ntracellular signaling pathways that mediate these various cellular respons es are not well understood. Here we report that angiogenin induces transien t phosphorylation of extracellular signal-related kinase1/2 (Erk1/2) in cul tured human umbilical vein endothelial cells. Angiogenin does not affect th e phosphorylation status of stress-associated protein kinase/c-Jun N-termin al kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinases. PD980 59-a specific inhibitor of MAP or Erk kinase 1 (MEK 1), the upstream kinase that phosphorylates Erk1/2-abolishes angiogenin-induced Erk phosphorylatio n and cell proliferation without affecting nuclear translocation of angioge nin. In contrast, neomycin, a known inhibitor of nuclear translocation and cell proliferation, does not interfere with angiogenin-induced Erk1/2 phosp horylation. These data indicate that both intracellular signaling pathways and direct nuclear functions of angiogenin are required for angiogenin-indu ced cell proliferation and angiogenesis. (C) 2001 A demi Press.