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

Ditte Marie Brix; Siri Amanda Tvingsholm; Malene Bredahl Hansen; Knut Bundgaard Clemmensen; Tiina Ohman; Valentina Siino; Matteo Lambrughi; Klaus Hansen; Pietri Puustinen; Irina Gromova; Peter James; Elena Papaleo; Markku Varjosalo; José Moreira; Marja Jäättelä; Tuula Kallunki

doi:10.1038/s41388-018-0653-x

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

Ditte Marie Brix, Siri Amanda Tvingsholm, Malene Bredahl Hansen, Knut Bundgaard Clemmensen, Tiina Ohman, Valentina Siino, Matteo Lambrughi, Klaus Hansen, Pietri Puustinen, Irina Gromova, Peter James, Elena Papaleo, Markku Varjosalo, José Moreira, Marja Jäättelä, Tuula Kallunki

9 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Oncogene
Vol/bind	38
Sider (fra-til)	3170-3184
ISSN	0950-9232
DOI	https://doi.org/10.1038/s41388-018-0653-x
Status	Udgivet - 25 apr. 2019

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10.1038/s41388-018-0653-x

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Brix, D. M., Tvingsholm, S. A., Hansen, M. B., Clemmensen, K. B., Ohman, T., Siino, V., Lambrughi, M., Hansen, K., Puustinen, P., Gromova, I., James, P., Papaleo, E., Varjosalo, M., Moreira, J., Jäättelä, M., & Kallunki, T. (2019). Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion. Oncogene, 38, 3170-3184. https://doi.org/10.1038/s41388-018-0653-x

Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion. / Brix, Ditte Marie; Tvingsholm, Siri Amanda; Hansen, Malene Bredahl et al.

I: Oncogene, Bind 38, 25.04.2019, s. 3170-3184.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Brix, DM, Tvingsholm, SA, Hansen, MB, Clemmensen, KB, Ohman, T, Siino, V, Lambrughi, M, Hansen, K, Puustinen, P, Gromova, I, James, P, Papaleo, E, Varjosalo, M, Moreira, J, Jäättelä, M & Kallunki, T 2019, 'Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion', Oncogene, bind 38, s. 3170-3184. https://doi.org/10.1038/s41388-018-0653-x

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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",

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month = apr,

day = "25",

doi = "10.1038/s41388-018-0653-x",

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T1 - Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion

AU - Brix, Ditte Marie

AU - Tvingsholm, Siri Amanda

AU - Hansen, Malene Bredahl

AU - Clemmensen, Knut Bundgaard

AU - Ohman, Tiina

AU - Siino, Valentina

AU - Lambrughi, Matteo

AU - Hansen, Klaus

AU - Puustinen, Pietri

AU - Gromova, Irina

AU - James, Peter

AU - Papaleo, Elena

AU - Varjosalo, Markku

AU - Moreira, José

AU - Jäättelä, Marja

AU - Kallunki, Tuula

PY - 2019/4/25

Y1 - 2019/4/25

N2 - 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.

AB - 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.

U2 - 10.1038/s41388-018-0653-x

DO - 10.1038/s41388-018-0653-x

M3 - Journal article

C2 - 30622337

SN - 0950-9232

VL - 38

SP - 3170

EP - 3184

JO - Oncogene

JF - Oncogene

ER -

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

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