Mammalian Grb2 Regulates Multiple Steps in Embryonic Development and Malignant Transformation

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.

Signal transduction in mammary tumorigenesis: a transgenic perspective

“…To determine the role Grb2 plays in MT induced carcinoma, the rate of mammary tumor formation was assessed in MMTV-PyV-MT transgenic animals containing a targeted grb2 mutation. Although a lack of Grb2 is incompatible with embryonic development (Cheng et al, 1998), mice bearing a single functional grb2 allele develop breast tumors with a delayed onset relative to wild-type littermate controls. Thus, Ras activation through the Shc-Grb2 complex appears to play a critical role in the rapid generation of mammary tumors.…”

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

“…Conversely, LIF acts by boosting expression of members of the network 22, 23, 24. Genetic perturbations have established that ERK1/2 signalling downstream of fibroblast growth factor 4 (FGF) is important for timely and efficient exit from the naïve state and subsequent commitment 15, 25, 26, 27, 28, 29, 30, 31. Consistent with this, inhibition of either FGF receptor or the MEK/ERK1/2 pathway markedly impedes ES cell differentiation 6, 32, 33.…”

GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells

“…Grb2 þ /À mice exhibit reduced susceptibility to FV Mice with a targeted deletion in the gene-encoding Grb2 are embryonic lethal (Cheng et al, 1998), however, haplo-insufficiency results in several defects in the adult animal including impaired negative selection of T cells, a block in cardiac hypertrophy and fibrosis in response to pressure overload and resistance to neointima formation following carotid injury (Gong et al, 2001;Zhang et al, 2003). In order to determine the susceptibility of Grb2 þ /À mice on a sensitive BALB/c background to FV in vivo, 8-week-old Grb2 þ /À and wild-type control mice were infected with FV and spleens were harvested 2 weeks later.…”