Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras.

Abstract

Several findings suggest that signals from tyrosine kinases are transduced, at least in part, through ras proteins. These findings include (i) blociage of the transforming activity of constitutively active tyrosine kinases by inhibing ras function and (it) genetic screens in Caenorhabdis elegans and in Drosophila that identified ras genes as downstream effectors of tyrosine kinases. The recently isoated Drosophila gene Son of sevenless (Sos) is postulated to act as a positive regulatory link between tyrosine kinase and ras proteins by catalyzing exchange of GDP for GTP on ras protein. Such exchange proteins have been reported in extracts of mammalian cells but have not been previously characterized at a molecular level. As Sos appears to function in this role in Drosophila, we sought to isolate a vertebrate counterpart(s). We have characterized two widely expressed murine genes with a high degree of homology to Sos. Hybridization with human DNA and RNA indicates a high degree of conservation of these genes in other vertebrates.Protein tyrosine kinases (PTKs) are a superfamily of genes whose protein products regulate many aspects of cellular proliferation, survival, and differentiation (1). Many of the extracellular ligands that modulate the activity of individual PTKs have been identified. However, less is known of the intracellular factors that interact either directly with the catalytic domain of tyrosine kinases or form more distal parts of the tyrosine kinase signaling pathway. There is compelling evidence (for review, see ref. 1) to suggest that proteins such as phospholipase C-y and the c-rafl seine threonine kinase are phosphorylated, and their activity is modulated, as a result of the activation of tyrosine kinases. Ras proteins have also been identified as important components in PTK signal transduction in mammalian cells (2, 3), Caenorhabditis elegans (4), and Drosophila (5, 6). However, these proteins must represent only some of the components of the tyrosine kinase signaling pathway.We have previously attempted to study the mechanism of signaling by PTKs by conducting a systematic genetic screen in Drosophila, involving the PTK receptor sevenless (5). Sevenless is required for the differentiation of R7 photoreceptor cells in the Drosophila eye. By creating circumstances where the sevenless signaling pathway was barely adequate for R7 formation, we were able to uncover mutations in several genes probably involved in signal transduction by the sevenless protein. Genetic analyses suggested that these genes are involved in additional developmental pathways in Drosophila. In particular, at least four genes appear to be also involved in signal transduction by another tyrosine kinase, the epidermal growth factor receptor. Of the four genes likely to be general components in tyrosine kinase signaling two have been characterized at a molecular level (5, 6). These are the Drosophila Rasl gene (7) and Son of sevenless (Sos, ref. 8).A region of the Sos gene shows a high degree of homology with several ye...

Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2

“…Similar to SH2 domains, the PID domain of Shc and other proteins has been shown to bind phosphotyrosine residues within the context of speci®c amino acid sequences (Kavanaugh and Williams, 1994;Blaikie et al, 1994;Pawson, 1994). Dab2 also contains a C-terminal proline-rich domain, the sequence of which resembles the proline-rich motifs contained in Sos (Bowtell et al, 1992;Chardin et al, 1993), a guanine nucleotide exchange factor for Ras (Scheme I).…”

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

“…Grb2 uses its SH2 domain to bind to phosphotyrosine residues found in EGFR or ErbB2, while it uses its SH3 domains to bind to proteins containing proline-rich motifs, such as Son of Sevenless (Sos) (Buday and Downward, 1993a,b;Lowenstein et al, 1992;Suen et al, 1993). Sos is a guanine nucleotide exchange factor, and is a positive regulator of Ras (Bon®ni et al, 1992;Bowtell et al, 1992). Ras is important for the regulation of various cellular processes, such as gene transcription and cellular proliferation.…”

Basis for Signaling Specificity Difference between Sos and Ras-GRF Guanine Nucleotide Exchange Factors

“…Most studies on Cdc25-like GEFs have investigated the Ras-activating Sos and Ras-GRF families. Sos1 and Sos2 are highly similar GEFs that contain Grb2-binding domains, allowing them to be activated by cell-surface tyrosine kinases (2,12). Ras-GRF1 (also referred to as Cdc25 Mm ) (13,14) and Ras-GRF2 (15) are also highly similar GEFs that contain calmodulin-binding domains, allowing them to be activated by elevated calcium in cells (16,17).…”