Polo-like kinase 4 accelerates glioma malignant progression and vasculogenic mimicry by phosphorylating EphA2

Vasculogenic mimicry (VM), which involved the formation of vascular-like structures by highly invasive tumor cells, had been identified as one of the mechanisms contributing to resistance against anti-angiogenic therapy in patients with glioblastoma (GBM). Therefore, inhibition of VM formation may serve as an effective therapeutic strategy against angiogenesis resistance. Polo-like kinase 4 (PLK4), a protein kinase, had been linked to the progression of glioblastoma and was associated with an unfavorable prognosis. The integration of proteomics and phosphoproteomics revealed that PLK4 directly activated the PI3K-Akt and MAPK signaling cascades by phosphorylating the Ser901 and Ser897 of EphA2. In addition, EphA2 Ser901 phosphorylating catalyzed by PLK4 significantly enhanced the phosphorylation of its own Ser897 site, which is a hallmark of EphA2 activation. The PI3K-Akt signaling was intricately associated with the progression of VM. Thus, PLK4 influenced malignant progression and VM formation via stimulation of the EphA2 signal transduction. Moreover, the expression level of PLK4 protein positively correlated with the level of EphA2 phosphorylation in glioma tissues. These results highlighted the crucial significance of PLK4 phosphorylating EphA2 in the malignant progression and VM formation in GBM.