Functions of fos phosphorylation in bone homeostasis, cytokine response and tumourigenesis

ABSTRACT Mice lacking _c-fos_ develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2

regulates Fos stability and transactivation potential _in vitro_. To assess the physiological relevance of Fos phosphorylation _in vivo_, serine 362 and/or serine 374 was replaced by alanine

(Fos362A, Fos374A and FosAA) or by phospho-mimetic aspartic acid (FosDD). Homozygous mutants were healthy and skeletogenesis was largely unaffected. Fos C-terminal phosphorylation,

predominantly on serine 374, was found important for osteoclast differentiation _in vitro_ and affected lipopolysaccharide (LPS)-induced cytokine response _in vitro_ and _in vivo_.

Importantly, skin papilloma development was delayed in FosAA, Fos362A and _Rsk2_-deficient mice, accelerated in FosDD mice and unaffected in Fos374A mutants. Furthermore, the related Fos

protein and putative RSK2 target Fra1 failed to substitute for Fos in papilloma development. This indicates that phosphorylation of serines 362 and 374 exerts context-dependent roles in

modulating Fos activity _in vivo_. Inhibition of Fos C-terminal phosphorylation on serine 362 by targeting RSK2 might be of therapeutic relevance for skin tumours. Access through your

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BEING VIEWED BY OTHERS MEF2C REGULATES OSTEOCLASTOGENESIS AND PATHOLOGIC BONE RESORPTION VIA C-FOS Article Open access 11 January 2021 WNT SIGNALING AND LOXL2 PROMOTE AGGRESSIVE OSTEOSARCOMA

Article Open access 20 July 2020 INHIBITION OF CDK5 INCREASES OSTEOBLAST DIFFERENTIATION AND BONE MASS AND IMPROVES FRACTURE HEALING Article Open access 06 April 2022 REFERENCES * Bakiri L,

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ACKNOWLEDGEMENTS We are very grateful to Drs K Matsuo, Y Takada and R Khokha for critical comments and helpful suggestions, Drs F Mulero and RP Marshall for help with micro-computed

tomography, U Moehle-Steinlein, E Andres, HC Theussl and V Komnenovic for technical assistance. The project was initiated at the IMP, which is funded by Boehringer Ingelheim (BI). EFW is

funded by the BBVA-Foundation and by an ERC advanced Grant. Part of this work was funded by an EMBO postdoctoral fellowship to LB and the NoE Cells into Organs (LSHM-CT-2003-504468) program

of the European Community. AUTHOR INFORMATION Author notes * R Zenz Present address: 5Current address: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria., * M O Reschke:

Currrent address: Division of Genetics, Beth Israel Deaconess Medical Center, Boston, MA, USA. AUTHORS AND AFFILIATIONS * Genes, Development and Disease Group, F-BBVA Cancer Cell Biology

programme, National Cancer Research Centre (CNIO), Madrid, Spain L Bakiri, M O Reschke, H A Gefroh, M H Idarraga, K Polzer, R Zenz, G Schett & E F Wagner * Research Institute of

Molecular Pathology (IMP), Vienna, Austria M H Idarraga * Department of Internal Medicine 3, University of Erlangen-Nurenberg, Erlangen, Germany K Polzer & G Schett Authors * L Bakiri

View author publications You can also search for this author inPubMed Google Scholar * M O Reschke View author publications You can also search for this author inPubMed Google Scholar * H A

Gefroh View author publications You can also search for this author inPubMed Google Scholar * M H Idarraga View author publications You can also search for this author inPubMed Google

Scholar * K Polzer View author publications You can also search for this author inPubMed Google Scholar * R Zenz View author publications You can also search for this author inPubMed Google

Scholar * G Schett View author publications You can also search for this author inPubMed Google Scholar * E F Wagner View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to E F Wagner. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Bakiri, L., Reschke, M., Gefroh, H. _et al._ Functions of Fos phosphorylation in bone homeostasis, cytokine response and

tumourigenesis. _Oncogene_ 30, 1506–1517 (2011). https://doi.org/10.1038/onc.2010.542 Download citation * Received: 16 August 2010 * Revised: 20 September 2010 * Accepted: 10 October 2010 *

Published: 29 November 2010 * Issue Date: 31 March 2011 * DOI: https://doi.org/10.1038/onc.2010.542 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * AP-1 * Fos * knock-in * mouse * phosphorylation