The interaction between elk-1 and mitotic kinases in brain tumors

Ets-like transcription factor 1 (Elk-1) is a member of E twenty-six (ETS) oncogene superfamily of transcription factors which is composed of nuclear phospho-proteins that have important roles in development and disease. Activation of Elk-1 requires phosphorylation in particular Serine 383, Serine 389 and Threonine 417 residues within the activation domain by mitogen-activated protein kinase (MAPK) pathway in regulation of immediate early genes upon mitogenic stimulation, as well as PI3K/AKT and Protein Kinase C (PKC) pathways. Elk-1 has been implicated in protecting cells from apoptosis and downregulating apoptosis-associated genes, thereby mediating cell survival. Furthermore, Akt-dependent phosphorylation of Elk-1 has been shown to be important for proliferation of glioblastoma cells. Recently Elk-1 was shown to also interact with mitotic kinase Aurora-A in a mitotic phase-dependent manner in brain tumor cell lines, and that Serine 383 phosphorylation was important for its mitotic spindle localization. Furthermore, in a Polo like kinase (Plk) phospho-proteome analysis, novel phosphoforms of Elk-1 were identified. Yet it was not clear whether interaction of Elk-1 with Aurora-A resulted in its phosphorylation, or whether it was involved with other mitotic kinases. In this study we showed for the first time that Elk-1 indeed could interact with not only mitotic kinase Aurora-A but also Aurora-B, Polo-like kinase Plk-1 and cyclin dependent kinase 1 (Cdk1) through the N-terminal amino acids 93-205 of Elk-1. It was also defined for the first time novel phosphorylations of Elk-1 and showed that mutagenesis of these residues interferes with not only its interaction with mitotic kinases, but also mitotic profile of brain tumor cell lines.