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bioRxiv · 10.1101/2021.09.02.458712

The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins

Daulat, A.·Wagner, M. S.·Audebert, S.·Kowalczewska, M.·Ariey-Bonnet, J.·Finetti, P.·Bertucci, F.·Camoin, L.·Borg, J.-P.
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Abstract

Upregulation of the developmental Wnt/planar cell polarity pathway is observed in many cancers and is associated with cancer development at early and late stages. We recently showed that PRICKLE1 and VANGL2, two core Wnt/PCP components, are overexpressed in triple negative breast cancer and associated with poor prognosis. PRICKLE1 is a cytoplasmic protein phosphorylated by the poorly described serine/threonine kinase MINK1 which triggers its localization at the plasma membrane, a key step for its function. Knockdown experiments have demonstrated that MINK1 and PRICKLE1 contribute to TNBC cell motility and spreading in vitro and in vivo. However, the identity of MINK1 substrates and the role of MINK1 enzymatic activity in this process have not yet been addressed issues. We carried out a phosphoproteomic strategy and identified novel MINK1 substrates including LL5{beta}. LL5{beta} is a membrane scaffold molecule that anchors microtubules at the cell cortex through its association with the plus-end MT proteins CLASPs to trigger focal adhesion disassembly. LL5{beta} is a prominent member of the MINK1-PRICKLE1 protein complex and is directly phosphorylated by MINK1 that promotes its interaction with CLASP. Using a kinase inhibitor, we demonstrate that the enzymatic activity of MINK1 is involved in the protein complex assembly and localization, and cell migration. Analysis of gene expression data show that the concomitant up-regulation of PRICKLE1 and LL5{beta} mRNA levels encoding MINK1 substrates is associated with a poor metastasis-free survival for TNBC patients. Altogether, our results suggest that MINK1 may represent a potential target in TNBC.

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Daulat, A., Wagner, M. S., Audebert, S., Kowalczewska, M., Ariey-Bonnet, J., Finetti, P., Bertucci, F., Camoin, L., Borg, J.-P.. 2021-09-03. The serine/threonine kinase MINK1 directly regulates the function of promigratory proteins. https://doi.org/10.1101/2021.09.02.458712

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