The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer

C Rey, B Faustin, I Mahouche, R Ruggieri, C Brulard, F Ichas, I Soubeyran, L Lartigue & F De Giorgi
Oncogene. 2015-05; 35: 3190-3200
DOI: 10.1038/onc.2015.379

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Often described as a mediator of cell cycle arrest or as a pro-apoptotic factor
in stressful conditions, the MAP3K ZAK (Sterile alpha motif and leucine
zipper-containing kinase) has also been proven to positively regulate epidermal
growth factor receptor (EGFR) and WNT signaling pathways, cancer cell
proliferation and cellular neoplastic transformation. Here, we show that both
isoforms of ZAK, ZAK-α and ZAK-β are key factors in cancer cell migration. While
ZAK depletion reduced cell motility of HeLa and HCT116 cells, its overexpression
triggered the activation of all three mitogen-activated protein kinases (MAPKs),
extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and
p38, as well as an increase in cell motion. On the contrary, the kinase-dead
mutants, ZAK-α K45M and ZAK-β K45M, were not able to provoke such events, and
instead exerted a dominant-negative effect on MAPK activation and cell migration.
Pharmacological inhibition of ZAK by nilotinib, preventing
ZAK-autophosphorylation and thereby auto-activation, led to the same results.
Activated by epidermal growth factor (EGF), we further showed that ZAK
constitutes an essential element of the EGF/ERK-dependent cell migration pathway.
Using public transcriptomic databases and tissue microarrays, we finally
established that, as strong factors of the EGFR signaling pathway, ZAK-α and/or
ZAK-β transcripts and protein(s) are frequently upregulated in colorectal adenoma
and carcinoma patients. Notably, gene set enrichment analysis disclosed a
significant correlation between ZAK+ colorectal premalignant lesions and gene
sets belonging to the MAPK/ERK and motility-related signaling pathways of the
reactome database, strongly suggesting that ZAK induces such pro-tumoral reaction
cascades in human cancers.


Auteurs Bordeaux Neurocampus