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Molecular and Cellular Biology, October 2000, p. 7735-7750, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Inhibition of ErbB-2 Mitogenic and Transforming Activity by RALT, a Mitogen-Induced Signal Transducer Which Binds to the ErbB-2 Kinase Domain†

Loredana Fiorentino,1,Dagger Chiara Pertica,1 Monia Fiorini,1 Claudio Talora,1,§ Marco Crescenzi,2,|| Loriana Castellani,3 Stefano Alemà,4 Piero Benedetti,5 and Oreste Segatto1,*

Laboratories of Immunology1 and Molecular Oncogenesis,2 Regina Elena Cancer Institute, 00158 Rome, Department of Neuroscience and INFM, University of Rome Tor Vergata, Rome,3 Institute of Cell Biology, CNR, 00137 Rome,4 and CNR, Campus Adriano Buzzati-Traverso, 00016 Monterotondo Scalo,5 Italy

Received 29 March 2000/Returned for modification 19 May 2000/Accepted 24 July 2000

The product of rat gene 33 was identified as an ErbB-2-interacting protein in a two-hybrid screen employing the ErbB-2 juxtamembrane and kinase domains as bait. This interaction was reproduced in vitro with a glutathione S-transferase fusion protein spanning positions 282 to 395 of the 459-residue gene 33 protein. Activation of ErbB-2 catalytic function was required for ErbB-2-gene 33 physical interaction in living cells, whereas ErbB-2 autophosphorylation was dispensable. Expression of gene 33 protein was absent in growth-arrested NIH 3T3 fibroblasts but was induced within 60 to 90 min of serum stimulation or activation of the ErbB-2 kinase and decreased sharply upon entry into S phase. New differentiation factor stimulation of mitogen-deprived mammary epithelial cells also caused accumulation of gene 33 protein, which could be found in a complex with ErbB-2. Overexpression of gene 33 protein in mouse fibroblasts inhibited (i) cell proliferation driven by ErbB-2 but not by serum, (ii) cell transformation induced by ErbB-2 but not by Ras or Src, and (iii) sustained activation of ERK 1 and 2 by ErbB-2 but not by serum. The gene 33 protein may convey inhibitory signals downstream to ErbB-2 by virtue of its association with SH3-containing proteins, including GRB-2, which was found to associate with gene 33 protein in living cells. These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer).

* Corresponding author. Mailing address: Laboratory of Immunology, Regina Elena Cancer Institute-CRS, Via delle Messi d'Oro 156/158, 00158 Rome, Italy. Phone: 39-06-49852533. Fax: 39-06-49852505. E-mail: segatto{at}ifo.it.

dagger Dedicated to the cherished memory of Stefania and Raffaele.

Dagger Present address: Apoptosis and Cell Death Program, The Burnham Institute, La Jolla, CA 92037.

§ Present address: Cutaneous Biology Research Center, Massachusets General Hospital and Harvard Medical School, Charlestown, MA 02129.

|| Present address: Laboratory of Comparative Toxicology and Ecotoxicology, ISS, 00161 Rome, Italy.

Molecular and Cellular Biology, October 2000, p. 7735-7750, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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