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N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation

Oncogene volume 26, pages 3551–3558 (2007)Cite this article

Abstract

c-Fos dephosphorylated on tyrosine (c-Fos), a component of the activator protein-1 (AP-1) family of transcription factors, is expressed at very low levels in resting cells. However, its expression is rapidly upregulated in cells undergoing G0 to S phase transition leading to AP-1-dependent gene transcription responses. In addition, cytoplasmic c-Fos associates to the endoplasmic reticulum (ER) membranes and activates phospholipid synthesis during cell growth and differentiation. Herein, it is shown that in T98G cells, c-Fos/ER association and consequently phospholipid synthesis activation is regulated by the phosphorylated state of c-Fos tyrosine (tyr) residues. The small amount of c-Fos present in quiescent T98G cells is tyr-phosphorylated and not ER-membrane bound. In growing cells, it is dephosphorylated, associated to ER membranes and promotes phospholipid synthesis activation. Impairing tyr-dephosphorylation abrogates phospholipid synthesis activation and reduces proliferation rates to those of quiescent cells. Substitution of tyr residues 10, 30, 106 and 337 evidence tyr 10 and 30 as relevant for this regulatory phenomenon. It is concluded that phosphorylation of tyr residues 10 and 30 of c-Fos regulate the rate of synthesis of phospholipids by regulating c-Fos/ER association.

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Abbreviations

c-Fos:

c-Fos dephosphorylated on tyrosine

CIAP:

calf intestine alkaline phosphatase

IB:

immunoblot assays

IP:

immunoprecipitation assays

PAO:

phenylarsine oxide

P-c-Fos:

tyrosine-phosphorylated c-Fos

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Acknowledgements

We thank S Deza and G Schachner for excellent technical assistance, C Mas for help with microscopy documentation and GB Borioli, ML Renner and G Gomez for helpful discussions. pDS56HisFos was a generous gift of T Curran. This work was supported by grants from the James S McDonnell Foundation, FONCyT, CONICET and SeCyT, Universidad Nacional de Córdoba. BLC is a Researcher and MMP a fellow of CONICET.

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  1. Departamento de Química Biológica, CIQUIBIC (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    M M Portal, G O Ferrero & B L Caputto

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  1. M M Portal
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  2. G O Ferrero
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  3. B L Caputto
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Correspondence to B L Caputto.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Portal, M., Ferrero, G. & Caputto, B. N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation. Oncogene 26, 3551–3558 (2007). https://doi.org/10.1038/sj.onc.1210137

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