Oncogenic MNK signalling regulates the metastasis suppressor NDRG1

Abstract

The protein N-myc down-regulated gene 1 (NDRG1) represses tumour metastasis. It is phosphorylated at several sites by serum and glucocorticoid-regulated kinase 1 (SGK1). Here we show that NDRG1 is also regulated by the oncogenic MAP kinase-interacting kinase (MNK) pathway, a target for cancer therapy.

Inhibiting MNKs increases the expression of NDRG1 protein and mRNA in breast cancer cells. MNK inhibition also decreases the phosphorylation of NDRG1. Phosphorylation of NDRG1 is reduced in cells lacking MNK1, but not MNK2-knockout cells, indicating that NDRG1 phosphorylation is a specific target for MNK1. However, MNK1 cannot directly phosphorylate NDRG1 in vitro, indicating that additional signalling connections are involved. Taken together, our data indicate that MNK signaling regulates NDRG1 at transcriptional and post-translational levels.

We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity. NDRG1, SGK1 and the MNKs are implicated in cell migration and metastasis. As expected, knocking-down NDRG1 promoted cell migration. However, whereas MNK inhibition impairs these processes irrespective of NDRG1 levels, SGK inhibition only did so in NDRG1-depleted cells. Thus, MNKs and SGK affect migration/invasion through distinct mechanisms.

Our data reveal several novel connections between signalling pathways important for tumour biology.