title: PKN3 is the major regulator of angiogenesis and tumor metastasis in mice.
abstract: PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin β1 and integrin α5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes.
authors.affiliation: Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mukai
authors.affiliation: Graduate School of Science and Technology, Kobe University, Kobe 657-8501, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Muramatsu
authors.affiliation: Graduate School of Medicine, Kobe University, Kobe 657-8501, Japan.
authors.forename: Rana
authors.initials: R
authors.lastname: Mashud
authors.affiliation: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kubouchi
authors.affiliation: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tsujimoto
authors.affiliation: Graduate School of Comprehensive Human Sciences, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Tsunaki
authors.initials: T
authors.lastname: Hongu
authors.affiliation: Graduate School of Comprehensive Human Sciences, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
authors.affiliation: Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies (CLST), 2-2-3 Minatojima Minami,Chuou-ku, Kobe 650-0047.
authors.forename: Go
authors.initials: G
authors.lastname: Shioi
authors.affiliation: Graduate School of Medicine, Kobe University, Kobe 657-8501, Japan.
authors.forename: Sally
authors.initials: S
authors.lastname: Danno
authors.affiliation: Graduate School of Medicine, Kobe University, Kobe 657-8501, Japan.
authors.forename: Mona
authors.initials: M
authors.lastname: Mehruba
authors.affiliation: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Satoh
authors.affiliation: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sugiura
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001681:Biological Assay; D018827:Carcinoma, Lewis Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003315:Cornea / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D039482:Integrin alpha5; D019012:Integrin beta1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018799:Intercellular Adhesion Molecule-1; C061570:protein kinase N; D011493:Protein Kinase C