title: Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control.
abstract: Over-expression studies have demonstrated that RALT (receptor associated late transducer) is a feedback inhibitor of ErbB-2 mitogenic and transforming signals. In growth-arrested cells, expression of endogenous RALT is induced by mitogenic stimuli, is high throughout mid to late G1 and returns to baseline as cells move into S phase. Here, we show that physiological levels of RALT effectively suppress ErbB-2 mitogenic signals. We also investigate the regulatory mechanisms that preside to the control of RALT expression. We demonstrate that pharmacological ablation of extracellular signal-regulated kinase (ERK) activation leads to blockade of RALT expression, unlike genetic and/or pharmacological interference with the activities of PKC, Src family kinases, p38 SAPK and PI-3K. Tamoxifen-dependent activation of an inducible Raf : ER chimera was sufficient to induce RALT expression. Thus, activation of the Ras-Raf-ERK pathway is necessary and sufficient to drive RALT expression. The RALT protein is labile and was found to accumulate robustly upon pharmacological inhibition of the proteasome. We were able to detect ubiquitin-conjugated RALT species in living cells, suggesting that ubiquitinylation targets RALT for proteasome-dependent degradation. Such an integrated transcriptional and post-translational control is likely to provide RALT with the ability to fluctuate timely in order to tune ErbB signals.
authors.affiliation: Laboratory of Immunology, Istituto Regina Elena, 00156 Rome, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Fiorini
authors.forename: Costanza
authors.initials: C
authors.lastname: Ballarò
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sala
authors.forename: Germana
authors.initials: G
authors.lastname: Falcone
authors.forename: Stefano
authors.initials: S
authors.lastname: Alemà
authors.forename: Oreste
authors.initials: O
authors.lastname: Segatto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C484017:ERRFI1 protein, human