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, Su Jae Lee

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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.

Original languageEnglish
Pages (from-to)4890-4902
Number of pages13
JournalOncotarget
Volume7
Issue number4
DOIs
Publication statusPublished - 2016 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Hwang, E., Yoo, K. C., Kang, S. G., Kim, R. K., Cui, Y. H., Lee, H. J., Kim, M. J., Lee, J. S., Kim, I. G., Suh, Y., & Lee, S. J. (2016). PKCδ activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling. Oncotarget, 7(4), 4890-4902. https://doi.org/10.18632/oncotarget.6640