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

Oncogene volume 35, pages 3190–3200 (2016)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the French National Institute for Medical Research (INSERM), Aquitaine Region, French Ministry of Research, Institut Bergonié, Association for Cancer Research (ARC), the Ligue Contre le Cancer, and Cancéropôle Grand Sud-Ouest, ‘Agir Cancer’ Gironde and The French National Research Agency (ANR). We thank Nicolas Faur, Raphael Moustié and Assia Chaibi for their technical help and Pippa McKelvie-Sebileau of Institut Bergonié for medical editorial assistance.

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  1. L Lartigue and F De Giorgi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Validation et Identification de Nouvelles Cibles en Oncologie (VINCO), INSERM U916, Institut Bergonié, Université Victor Segalen Bordeaux 2, Bordeaux, France

    C Rey, I Mahouche, C Brulard & L Lartigue

  2. CNRS – CIRID, Bordeaux Cedex, France

    B Faustin

  3. Laboratory of Cell Signaling, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    R Ruggieri

  4. Fluofarma, 2 rue R. Escarpit, Pessac, France

    F Ichas & F De Giorgi

  5. Département de Biopathologie, Institut Bergonié, Bordeaux, France

    I Soubeyran

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Rey, C., Faustin, B., Mahouche, I. et al. The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer. Oncogene 35, 3190–3200 (2016). https://doi.org/10.1038/onc.2015.379

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