1. Mammalian Grb2 Regulates Multiple Steps in Embryonic Development and Malignant Transformation
- Author
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Alec M. Cheng, Wolfgang F. Vogel, James C. Cross, Tracy M. Saxton, Tony Pawson, Christopher G. Tortorice, Sarang Kulkarni, William J. Muller, Geraldine Mbamalu, Ryuichi Sakai, and Robert D. Cardiff
- Subjects
Male ,animal structures ,Cellular differentiation ,Antigens, Polyomavirus Transforming ,Biology ,SH2 domain ,General Biochemistry, Genetics and Molecular Biology ,SH3 domain ,Mice ,Animals ,Guanine Nucleotide Exchange Factors ,Humans ,Adaptor Proteins, Signal Transducing ,GRB2 Adaptor Protein ,Mammals ,Biochemistry, Genetics and Molecular Biology(all) ,Endoderm ,Signal transducing adaptor protein ,Mammary Neoplasms, Experimental ,Proteins ,Cell Differentiation ,Molecular biology ,Fusion protein ,Cell biology ,Artificial Gene Fusion ,Cell Transformation, Neoplastic ,Epiblast ,Gene Targeting ,biology.protein ,ras Proteins ,Female ,ras Guanine Nucleotide Exchange Factors ,GRB2 ,biological phenomena, cell phenomena, and immunity ,Cell Division - 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.
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