Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase

Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells

“…Loss of function mutations in the Drosophila and Caenorhabditis elegans homologues of GRB2 disrupt signaling by the Sevenless and Let-23 receptor tyrosine kinases, respectively, and the mutant phenotypes can be speci®cally rescued by expression of wildtype GRB2 (Clark et al, 1992;Simon et al, 1991Simon et al, , 1993Stern et al, 1993). Grb2 is critical for the transformation of ®broblasts by RTKs (Lowenstein et al, 1992;Pendergast et al, 1993;Xie et al, 1995), and for the proliferation of chronic myelogenous leukemic cells, which are regulated by the constitutively active Bcr-Abl tyrosine kinase (Tari et al, 1997).…”

New insights into protein‐tyrosine kinase receptor signaling complexes

“…The Sos protein was described originally as a signaling molecule that acted downstream of the Sevenless PTK receptor, a requirement for the proper specification of R7 photoreceptor cells in the eye of Drosophila. In addition to proline-rich motifs, Sos was shown to contain sequences related to known Ras guanine-nucleotide exchange proteins (GNRP) (Simon et al, 1991). It would appear that Grb-2 and Sos proteins are associated constitutively, but only function to activate Ras upon receptor stimulation.…”

Activation of Ras and its downstream extracellular signal-regulated protein kinases by the CDC25 homology domain of mouse Son-of-sevenless 1 (mSos1)

“…Formation of GTP-bound Ras is promoted by guanine nucleotide exchange factors (GEFs), such as the mouse and human Son-of-sevenless proteins (mSos and hSos, respectively) (Bowtell et al, 1992;Chardin et al, 1993). These Sos proteins were identi®ed as the homologs of the Drosophila melanogaster Sos (dSos), which mediates the signal from the Sevenless receptor tyrosine kinase to Ras1 in the R7 cell development of the Drosophila eye (Simon et al, 1991). In Saccharomyces cerevisiae cells, the CDC25 protein serves as a Ras GEF (Broek et al, 1987).…”