Research Papers:

PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling

Eunji Hwang, Ki-Chun Yoo, Seok-Gu Kang, Rae-Kwon Kim, Yan-Hong Cui, Hae-June Lee, Min-Jung Kim, Jae-Seong Lee, In-Gyu Kim, Yongjoon Suh and Su-Jae Lee _

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Oncotarget. 2016; 7:4890-4902. https://doi.org/10.18632/oncotarget.6640

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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

Correspondence to:

Su-Jae Lee, e-mail: sj0420@hanyang.ac.kr

Yongjoon Suh, e-mail: hiswork@hanmail.net

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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