N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation.
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 G(0) 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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CIQUIBIC (CONICET), Facultad de Ciencias Químicas, Departamento de Química Biológica, Universidad Nacional de Córdoba, Córdoba, Argentina.
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D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D010743:Phospholipids / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D010743:Phospholipids; D011500:Protein Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D014443:Tyrosine; D003513:Cycloheximide