suppression of apoptosis (Franke et al., 1997), reorganization of the actin cytoskeleton (Rodriguez-Viciana et al., 1997), cardiac myocyte growth (Shioi et al., 2000), glycogen synthase stimulation by insulin (reviewed in Shepherd et al., 1998), TNFa-mediated neutrophil primMichael E. Pacold,* Sabine Suire,† Olga Perisic,* Samuel Lara-Gonzalez,* Colin T. Davis,* Edward H. Walker,* Phillip T. Ha...

Protein palmitoylation, the thioester linkage of fatty acyl moieties (typically, saturated 16C palmitate) to cysteine, is a lipid modification that serves both to tether proteins to membranes and to direct their localization to membrane microdomains. Unlike the two other types of lipid modification that also tether proteins to cytosolic membrane surfaces, namely prenylation and myristoylation, ...

Ras activation and mitochondrial dysfunction (green) stimulate cell proliferation (magenta) of surrounding cells (blue). Image courtesy of Tatsushi Igaki. Inhibiting Hippo Helps Neighbors Grow Cell-autonomous growth control has been extensively studied in cancer; however, the mechanisms through which cancer cells influence their neighbors’ growth are poorly understood. A new study by Ohsawa et ...

It is of great therapeutic importance to understand why tumors relapse after the failure of therapies targeting oncogenes to which cancer cells are addicted. In this issue, Kapoor et al. and Shao et al. identify the transcriptional coactivator YAP1 as a central driver of compensation for the loss of K-Ras signaling in K-Ras-dependent cancers.

Activated ras genes have been implicated in a wide variety of neoplasms [2]. N-ras in particular has been shown to be involved in acute myelogenous leukaemia (AML) with activating mutations around codons 12/13 and 61 [3, 7]. The myelodysplastic syndromes (MDS) are a group of preleukaemias, a proportion of which will develop AML. Hirai et al. [9] described three MDS patients with N-ras mutations...

The concept that Ras proteins may function as oligomers was first described almost three decades ago when Santos et al. (1) found evidence for wild-type or mutant H-Ras multimerization using radiation inactivation assays. The idea was largely dropped when the myriad of crystal structures of H-Ras that followed over the ensuing decades suggested that Ras proteins are functional monomers. Inouye ...

Neurofibromatosis type 1 (NF1) is a relatively common genetic disease that is associated with a variety of neurologic complications. In addition to irregularities such as the formation of neurofibromas and neurofibrosarcomas, NF1 patients also suffer increased incidence of chronic pain (Creange et al. 1999; Wolkenstein et al. 2001). In this issue of the Journal of Neurophysiology (p. 3670-3676)...

A clinically efficacious Ras inhibitor has eluded drug-discovery efforts for decades. In a paper in Nature, Zimmermann and et al. show that blocking a hole in PDEδ that normally engages the lipid tail of Ras disrupts downstream signaling, pointing to a potentially promising route to develop Ras inhibitors for cancer treatment.

Ras interacts with many downstream effectors that regulate complex cytoplasmic signaling networks. In this issue, Gupta et al. (2007) use mouse models of Ras-mediated tumorigenesis to show that the interaction of Ras with a single isoform of phosphatidylinositol 3-kinase (PI3K), called p110alpha (PIK3CA), is critical for tumor formation. This result will stimulate re-evaluation of pharmacologic...

Ras makes a pit stop R as proteins are restless, continually fl itting from the cell membrane to the Golgi apparatus and back again. Misaki et al. reveal that the proteins enter recycling endosomes during the journey to the plasma membrane. One mystery is why Ras proteins—which spur cell growth, differentiation, and survival—move so often. The cluttered cell interior has also made it diffi cult...