MELK Signaling Pathway

1. MELK Signaling Pathway As a regulator, MELK interacts a wide range of proteins and activates some proteins via phosphorylation. It binds tightly to the zinc finger-like protein 9 (ZPR9) and then phosphorylates it, which causes its nuclear accumulation. ZPR9 interacts with the transcription factor v-MYB avian myeloblastosis viral oncogene homolog 2 (B-Myb) in the nucleus. B-Myb is an important regulator of cell differentiation and proliferation. In such case, MELK indirectly enhances its transcriptional activity. At the same time, MELK also interacts with nuclear inhibitor of protein Ser/Thr phosphatase-1 (NIPP1) that is a transcription and splicing factor. MELK functions by binding a threonine-phosphorylated motif to FHA domain of NIPP1. This MELK-NIPP1 interaction is more significant during the process of mitosis, which leads to an inhibition of pre-mRNA splicing. In addition, it also phosphorylates PDK1 at threonine 354 after the interaction, which highly inhibits its activity. CDC25B, another target protein of MELK, is a protein-tyrosine phosphatase that triggers mitosis by activating protein kinase CDK1. In cancer, MELK plays an essential part. It has the interaction with p53 that is of paramount importance in cancer-related regulations. Through the phosphorylation of Ser15 in the amino-terminal transactivation domain of p53, MELK enhances the stability and activity of p53. This further enhances 53-dependent apoptosis and cell cycle arrest. In melanoma cells, MELK is activated by E2F1 which directly binds to the MELK promoter and increases its level of transcription. E2F1 expression is stimulated by MAPK pathway. MELK can phosphorylate many proteins which are substrates of BRAF or MEK. The inhibition of MELK stops the growth of melanoma and it is resistant to vemurafenib, one of the BRAF inhibitors. In addition, NF-kB pathway can be regulated by MELK via Sequestosome 1 SQSTM1.