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The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity

Oncogene volume 31, pages 3381–3391 (2012)Cite this article

Abstract

Our previous work showed that in T98G cells, a human glioblastoma multiforme-derived cell line, the association of c-Fos to the endoplasmic reticulum (ER) and consequently, the capacity of c-Fos to activate phospholipid synthesis, is regulated by the phosphorylation state of tyrosine (tyr) residues #10 and #30 of c-Fos. The small amount of c-Fos present in quiescent cells is tyr-phosphorylated, is dissociated from the ER membranes and does not activate phospholipid synthesis. However, on induction of the cell to re-enter growth, c-Fos expression is rapidly induced, it is found dephosphorylated, associated to ER membranes and activating phospholipid synthesis (Portal et al., 2007). Herein, using in vivo and in vitro experimental strategies, we show that the kinase c-Src is capable of phosphorylating tyr residues of c-Fos whereas the phosphatase TC45 T-cell protein-tyr phosphatase (TC-PTP) dephosphorylates them, thus enabling c-Fos/ER association and activation of phospholipid synthesis. Results also suggest that the regulation of the phosphorylation/dephosphorylation cycle of c-Fos occurs at the TC-PTP level: induction of cells to re-enter growth promotes the translocation of TC45 from a nuclear to a cytoplasmic location concomitant with its activation. Activated TC45 in its turn promotes dephosphorylation of pre-formed c-Fos, enabling cells to rapidly activate phospholipid synthesis to respond to its growth demands.

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Acknowledgements

We thank HJF Maccioni for helpful discussions and H Carbonneau (Pardue University, West Lafayette, IN, USA) for providing pET-TC45a. pCG-TC45 and pCG-D182A were kind gifts from T Tiganis (Cold Spring Harbor Laboratory, New York, NY, USA) and pET-c-Src from MA Seelinger (University of California, Berkeley, CA, USA). Excellent technical assistance from Susana Deza and Gabriela Schachner is acknowledged. This work was supported by grants from the ANPCyT and CONICET, Ministerio de Ciencia, Tecnología e Innovación Productiva de Argentina, SECyT-Universidad Nacional de Córdoba, Argentina and the JS McDonnell Foundation. BLC is a career member and GOF and FV are fellows of CONICET.

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

    G O Ferrero, F N Velazquez & B L Caputto

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  1. G O Ferrero
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  2. F N Velazquez
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  3. B L Caputto
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Correspondence to B L Caputto.

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Ferrero, G., Velazquez, F. & Caputto, B. The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity. Oncogene 31, 3381–3391 (2012). https://doi.org/10.1038/onc.2011.510

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