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Science 13 May 1994:
Vol. 264. no. 5161, pp. 971 - 974
DOI: 10.1126/science.8178156
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Articles

Science, Vol 264, Issue 5161, 971-974
Copyright © 1994 by American Association for the Advancement of Science

articles

Cloning of a Grb2 isoform with apoptotic properties

I Fath, F Schweighoffer, I Rey, MC Multon, J Boiziau, M Duchesne, and B Tocque

Rhone-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.

Growth factor receptor-bound protein 2 (Grb2) links tyrosine-phosphorylated proteins to a guanine nucleotide releasing factor of the son of sevenless (Sos) class by attaching to the former by its Src homology 2 (SH2) moiety and to the latter by its SH3 domains. An isoform of grb2 complementary DNA (cDNA) was cloned that has a deletion in the SH2 domain. The protein encoded by this cDNA, Grb3-3, did not bind to phosphorylated epidermal growth factor receptor (EGFR) but retained functional SH3 domains and inhibited EGF-induced transactivation of a Ras-responsive element. The messenger RNA encoding Grb3-3 was expressed in high amounts in the thymus of rats at an age when massive negative selection of thymocytes occurs. Microinjection of Grb3-3 into Swiss 3T3 fibroblasts induced apoptosis. These findings indicate that Grb3-3, by acting as a dominant negative protein over Grb2 and by suppressing proliferative signals, may trigger active programmed cell death.


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