Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control

Monia Fiorini, Costanza Ballarò, Gianluca Sala, Germana Falcone, Stefano Alemà, Oreste Segatto

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6530-6539
Number of pages10
JournalOncogene
Volume21
Issue number42
DOIs
Publication statusPublished - Sep 19 2002

Keywords

  • Cell cycle
  • ErbB
  • Proteasome
  • RALT
  • Ras pathways

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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