Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation

Alec M. Cheng, Tracy M. Saxton, Ryuichi Sakai, Sarang Kulkarni, Geraldine Mbamalu, Wolfgang Vogel, Christopher G. Tortorice, Robert Cardiff, James C. Cross, William J. Muller, Tony Pawson

Research output: Contribution to journalArticle

282 Scopus citations

Abstract

Proteins with SH2 and SH3 domains link tyrosine kinases to intracellular pathways. To investigate the biological functions of a mammalian SH2/SH3 adaptor, we have introduced a null mutation into the mouse gene for Grb2. Analysis of mutant embryonic stem cells, embryos, and chimeras reveals that Grb2 is required during embyrogenesis for the differentiation of endodermal cells and formation of the epiblast. Grb2 acts physiologically as an adaptor, since replacing the C terminus of the Ras activator Sos1 with the Grb2 SH2 domain yields a fusion protein that largely rescues the defects caused by the Grb2 mutation. Furthermore, Grb2 is rate limiting for mammary carcinomas induced by polyomavirus middle T antigen. These data provide genetic evidence for a mammalian Grb2-Ras signaling pathway, mediated by SH2/SH3 domain interactions, that has multiple functions in embryogenesis and cancer.

Original languageEnglish (US)
Pages (from-to)793-803
Number of pages11
JournalCell
Volume95
Issue number6
DOIs
StatePublished - Dec 11 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Cheng, A. M., Saxton, T. M., Sakai, R., Kulkarni, S., Mbamalu, G., Vogel, W., Tortorice, C. G., Cardiff, R., Cross, J. C., Muller, W. J., & Pawson, T. (1998). Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell, 95(6), 793-803. https://doi.org/10.1016/S0092-8674(00)81702-X