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.
Highlights
Glioblastomas multiforme (GBM) is the most aggressive form of primary brain tumors with their tendency to invade surrounding healthy brain parenchyma, rendering them largely incurable
We showed that PKCδ was aberrantly activated in GBM cells by c-MET, a receptor tyrosine kinase hyperactivated in GBM
We found that among Protein kinase C (PKC) isoforms, PKCδ contributes to GBM cell invasiveness
Summary
Glioblastomas multiforme (GBM) is the most aggressive form of primary brain tumors with their tendency to invade surrounding healthy brain parenchyma, rendering them largely incurable. Protein kinase C (PKC) constitutes a family of serine/threonine kinases activated by a variety of external stimuli, such as hormones, growth factors and other membrane receptor ligands, that transduce intracellular signaling through phosphorylation of a large number of protein substrates[2] Based on their structure and activation characteristics, the PKC family is classified into three subfamilies: classical or conventional PKC isozymes (PKCα, PKCβI, PKCβII and PKCγ), nonclassical or novel PKC isozymes (PKCδ, PKCε, PKCη and PKCθ), and atypical PKC isozymes (PKCζ, PKCι www.impactjournals.com/oncotarget and PKCλ)[3]. The same PKC isozyme can have opposing roles in cancer, presumably due to complexity of their interactions with numerous substrates and the many secondary messenger systems coupled with their cellular and tissuespecific variability [2, 7]
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