Inhibition of Ras-stimulating enzymes is a possible avenue to treat Ras-driven diseases. In this issue of Chemistry & Biology, Evelyn and coworkers report an inhibitor for one such enzyme, Sos1, capable of impairing wild-type Ras signaling in cells.

A large genetic screen for sos (for salt overly sensitive) mutants was performed in an attempt to isolate mutations in any gene with an sos phenotype. Our search yielded 28 new alleles of sos1, nine mutant alleles of a newly identified locus, SOS2, and one allele of a third salt tolerance locus, SOS3. The sos2 mutations, which are recessive, were mapped to the lower arm of chromosome V, approxi...

Thymocytes convert graded T cell receptor (TCR) signals into positive selection or deletion, and activation of extracellular signal-related kinase (ERK), p38, and Jun N-terminal protein kinase (JNK) mitogen-activated protein kinases (MAPKs) has been postulated to play a discriminatory role. Two families of Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP, activate Ras and the d...

The SH2 and SH3 domain structural integrity and functionality were confirmed by peptide binding assays. Binding studies using two phosphotyrosine peptides derived from EGFR (FLPVPE{pY}IN-QSVPKR) and Shc (EEPPDHQ{pY}YNDFPGK) for the Grb2 SH2 domain and a SOS1-derived proline-rich peptide (PVPPPVPPRRRPEY) for the SH3 domains were performed using MST 1. Grb2 was fluorescently labeled using Atto488...

To understand the mechanisms by which electrical activity may generate long-term responses in the nervous system, we examined how activation of voltage-sensitive calcium channels (VSCCs) can stimulate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Calcium influx through L-type VSCCs leads to tyrosine phosphorylation of the adaptor protein Shc and its association with the ada...

The human airway is lined with respiratory epithelial cells, which create a critical barrier through the formation of apical tight junctions. To investigate the molecular mechanisms underlying this process, an RNAi screen for guanine nucleotide exchange factors (GEFs) was performed in human bronchial epithelial cells (16HBE). We report that SOS1, acting through the Ras/MEK/ERK pathway, is essen...