title: PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling.
abstract: Poor prognosis of glioblastoma (GBM) is attributable to the propensity of tumor cells to infiltrate into the brain parenchyma. Protein kinase C (PKC) isozymes are highly expressed or aberrantly activated in GBM. However, how this signaling node translates to GBM cell invasiveness remains unknown. Here, we report that among PKC isoforms, PKCδ is strongly associated with infiltration of GBM cells. Notably, PKCδ enhanced Tyr418 phosphorylation of the non-receptor tyrosine kinase SRC, which in turn activated STAT3 and subsequent NOTCH2 signaling, ultimately leading to GBM cell invasiveness. Furthermore, we showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM. In agreement, inhibition either component in the c-MET/PKCδ/SRC/STAT3 signaling axis effectively blocked the NOTCH2 signaling and invasiveness of GBM cells. Taken together, our findings shed a light on the signaling mechanisms behind the constitutive activation of PKCδ signaling in GBM.
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Ki-Chun
authors.initials: KC
authors.lastname: Yoo
authors.affiliation: Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Korea.
authors.forename: Seok-Gu
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Rae-Kwon
authors.initials: RK
authors.lastname: Kim
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Cui
authors.affiliation: Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, College of Science, Sungkyunkwan University, Seoul, Korea.
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Yongjoon
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C497764:NOTCH2 protein, human; D012333:RNA, Messenger; D051883:Receptor, Notch2; D019859:Proto-Oncogene Proteins c-met; D051745:Protein Kinase C-delta
keywords: NOTCH2; PKCδ; c-MET; glioblastoma; infiltration