Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion

Research output: Contribution to journalArticle

Bibtex

@article{36ce380c4fbf464ab3b148a5f501e0bf,
title = "Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion",
abstract = "HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.",
author = "Brix, {Ditte Marie} and Tvingsholm, {Siri Amanda} and Hansen, {Malene Bredahl} and Clemmensen, {Knut Bundgaard} and Tiina Ohman and Valentina Siino and Matteo Lambrughi and Klaus Hansen and Pietri Puustinen and Irina Gromova and Peter James and Elena Papaleo and Markku Varjosalo and Jos{\'e} Moreira and Marja J{\"a}{\"a}ttel{\"a} and Tuula Kallunki",
year = "2019",
month = "1",
day = "8",
doi = "10.1038/s41388-018-0653-x",
language = "English",
journal = "Oncogene",
issn = "1476-5594",
publisher = "Nature Publishing Group",

}