PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling
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Eunji Hwang1,*, Ki-Chun Yoo1,*, Seok-Gu Kang2, Rae-Kwon Kim1, Yan-Hong Cui1, Hae-June Lee3, Min-Jung Kim4, Jae-Seong Lee5, In-Gyu Kim6, Yongjoon Suh1, Su-Jae Lee1
1Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
2Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Korea
3Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
4Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
5Department of Biological Sciences, College of Science, Sungkyunkwan University, Seoul, Korea
6Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea
*These authors have contributed equally to this work
Su-Jae Lee, e-mail: firstname.lastname@example.org
Yongjoon Suh, e-mail: email@example.com
Keywords: PKCδ, infiltration, glioblastoma, NOTCH2, c-MET
Received: August 18, 2015 Accepted: December 05, 2015 Published: December 17, 2015
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.
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