title: A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis.
abstract: The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in both suppression and promotion of tumorigenesis. It remains unclear how these 2 opposite functions of p38 operate in vivo to impact cancer development. We previously reported that a p38 downstream kinase, p38-regulated/activated kinase (PRAK), suppresses tumor initiation and promotion by mediating oncogene-induced senescence in a murine skin carcinogenesis model. Here, using the same model, we show that once the tumors are formed, PRAK promotes the growth and progression of skin tumors. Further studies identify PRAK as a novel host factor essential for tumor angiogenesis. In response to tumor-secreted proangiogenic factors, PRAK is activated by p38 via a vascular endothelial growth factor receptor 2 (VEGFR2)-dependent mechanism in host endothelial cells, where it mediates cell migration toward tumors and incorporation of these cells into tumor vasculature, at least partly by regulating the phosphorylation and activation of focal adhesion kinase (FAK) and cytoskeletal reorganization. These findings have uncovered a novel signaling circuit essential for endothelial cell motility and tumor angiogenesis. Moreover, we demonstrate that the tumor-suppressing and tumor-promoting functions of the p38-PRAK pathway are temporally and spatially separated during cancer development in vivo, relying on the stimulus, and the tissue type and the stage of cancer development in which it is activated.
authors: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors: Naoto
authors: N
authors: Yoshizuka
authors: Rebecca M
authors: RM
authors: Chen
authors: Zeyu
authors: Z
authors: Xu
authors: Rong
authors: R
authors: Liao
authors: Lixin
authors: L
authors: Hong
authors: Wen-Yuan
authors: WY
authors: Hu
authors: Guoliang
authors: G
authors: Yu
authors: Jiahuai
authors: J
authors: Han
authors: Longchuan
authors: L
authors: Chen
authors: Peiqing
authors: P
authors: Sun
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002277:Carcinoma / Q000098:blood supply* / Q000139:chemically induced; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism*; D010212:Papilloma / Q000098:blood supply* / Q000139:chemically induced; D010704:Phorbols / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012878:Skin Neoplasms / Q000098:blood supply* / Q000139:chemically induced; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; D010704:Phorbols; D015127:9,10-Dimethyl-1,2-benzanthracene; C111049:MAP-kinase-activated kinase 5; D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C033085:phorbol