While ERK signaling to the nucleus has been shown to be required for gene transcription and cell cycle entry (Brunet et al., 1999), recent work has highlighted a requirement for ERK dimers in cytoplasmic, but not nuclear ERK signaling. of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration, and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis. gene has two splice variants, K-RasA and K-RasB, with K-RasB having higher expression and enzymatic activity. Knockout studies in mice have shown that both and are not required for overall mouse development, viability or fertility, even when both are knocked out at the same time, although fewer mice than normal survive embryogenesis in the double knockouts (Esteban et al., 2001). These results suggest that is the primary gene that is required for normal function in mouse development, although may have some role in viability. Initial knockout of in mice showed that embryos died between day 12.5 and term and that at day 11.5 they showed motor neuron cell death in the medulla and cervical spinal cord (Koera et al., 1997). Additionally, at day 15.5 these knockout mice had thin ventricular walls. These results exhibited a role for the entire gene for proper heart and neuronal development. However, this study did not take into account the potential differential effects of deletion of versus and found that these mouse displayed normal viability and fertility (Plowman et al., 2003). These results exhibited an essential role for the gene in mouse development. Open in a separate window Physique 1 Schematic showing the activation of the Ras to ERK pathway by growth factor binding to a receptor tyrosine kinase. Ligand binding induces receptor dimerization and autophosphorylation. The Grb2 adapter protein binds to activated receptors and increases association of the guanine nucleotide exchange factor Sos to Ras, resulting in Ras loading of GTP and activation. Ras enhances membrane recruitment and activation of the Raf protein kinases, which activate MEKs, leading to ERK activation. Once activated, ERKs phosphorylate cytoplasmic substrates and translocate to the nucleus to phosphorylate nuclear targets. In unstimulated cells and quiescent cells, Ras proteins primarily exist in an inactive state at the plasma membrane, bound to GDP (guanosine diphosphate), having hydrolyzed the gamma phosphate off of GTP from a previous state of protein activation. In order to achieve membrane localization, which is necessary for Ras proteins to become activated and signal, Ras proteins undergo a complex series of post-translational modifications that increase their hydrophobicity, allowing them to associate with the lipid bilayer. Ras proteins are synthesized with a CAAX motif at the C-terminus, where C is usually cysteine, A is an aliphatic amino acid and X is usually any amino acid at this C-terminal position. This sequence serves as a recognition motif for Ras modification, first by proteolytic cleavage of the AAX sequence by Ras converting enzyme (Rce1). This occurs for all four Ras isoforms mentioned above. These Ras proteins then undergo addition of a 15 carbon farnesyl group by a farnesyltransferase group to the now C-terminal cysteine residue, catalyzed by a farnesyltransferase. This altered cysteine then undergoes methylation by a isoprenylcysteine carboxyl methyltransferase (ICMT). K-RasB undergoes no additional isoprenoid modification and becomes membrane localized with the help of the farnesyl group and a polylysine sequence just N terminal to the terminal cysteine in a region called the hypervariable region CAY10471 Racemate that enhances the conversation of K-RasB with anionic phospholipids within membranes. This polylysine domain name has been shown to ensure K-RasB membrane binding and is important for its transforming ability (Hancock, Paterson, & Marshall, 1990; Jackson, Li, Buss, Der, & Cochrane, 1994). Mutation of the lysines to arginines, preserving the positive charges of these residues, allowed K-RasB to maintain its CAY10471 Racemate full CAY10471 Racemate transforming potential in NIH3T3 and Rat-1 cell lines mutations occur in 30% of all human cancers and up to IL1F2 95% in cancers such as pancreatic cancer (Bryant, Mancias, Kimmelman, & Der, 2014). mutations, particularly in in mice resulted in embryonic lethality (Hatano et al., 2003; Saba-El-Leil et al., 2003; Yao et al., 2003), while knockout of resulted in live births of mice that were fertile and initially only exhibited a deficiency in maturation of CD4CD8 thymocytes (Pages et al., 1999). These strong phenotypic differences.