Feedback inhibition by RALT controls signal output by the ErbB network

Sergio Anastasi, Loredana Fiorentino, Monia Fiorini, Rocco Fraioli, Gianluca Sala, L. Castellani, Stefano Alemà, Maurizio Alimandi, Oreste Segatto

Research output: Contribution to journalArticle

Abstract

The ErbB-2 interacting protein receptor-associated late transducer (RALT) was previously identified as a feedback inhibitor of ErbB-2 mitogenic signals. We now report that RALT binds to ligand-activated epidermal growth factor receptor (EGFR), ErbB-4 and ErbB-2.ErbB-3 dimers. When ectopically expressed in 32D cells reconstituted with the above ErbB receptor tyrosine kinases (RTKs) RALT behaved as a pan-ErbB inhibitor. Importantly, when tested in either cell proliferation assays or biochemical experiments measuring activation of ERK and AKT, RALT affected the signalling activity of distinct ErbB dimers with different relative potencies. RALT AEBR, a mutant unable to bind to ErbB RTKs, did not inhibit ErbB-dependent activation of ERK and AKT, consistent with RALT exerting its suppressive activity towards these pathways at a receptor-proximal level. Remarkably, RALT ΔEBR retained the ability to suppress largely the proliferative activity of ErbB-2.ErbB-3 dimers over a wide range of ligand concentrations, indicating that RALT can intercept ErbB-2.ErbB-3 mitogenic signals also at a receptor-distal level. A suppressive function of RALT ΔEBR towards the mitogenic activity of EGFR and ErbB-4 was detected at low levels of receptor occupancy, but was completely overcome by saturating concentrations of ligand. We propose that quantitative and qualitative aspects of RALT signalling concur in defining identity, strength and duration of signals generated by the ErbB network.

Original languageEnglish
Pages (from-to)4221-4234
Number of pages14
JournalOncogene
Volume22
Issue number27
DOIs
Publication statusPublished - Jul 3 2003

Keywords

  • ErbB
  • Feedback inhibition
  • Mig-6
  • Negative signaling
  • RALT

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Anastasi, S., Fiorentino, L., Fiorini, M., Fraioli, R., Sala, G., Castellani, L., Alemà, S., Alimandi, M., & Segatto, O. (2003). Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene, 22(27), 4221-4234. https://doi.org/10.1038/sj.onc.1206516