The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the “triple membrane bypass” pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.     

Induction of hemopoietic chimerism in the caprine fetus by intraperitoneal injection of fetal liver cells

Summary Intraperitoneal injection of allogeneic liver cells from 43-day-old male fetuses into normal 60-day female goat fetuses resulted in persistent hemopoietic chimerism in surviving recipients without clinical evidence of graft-versus-host disease. Transplantation of normal fetal liver cells into preimmunocompetent goat fetuses affected with -D-mannosidosis may provide an alternative strategy for evaluating hemopoietic stem cell transplantation in the treatment of human lysosomal storage diseases.     

FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.     

The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism

Here we present a draft genome sequence of the nematode Pristionchus pacificus, a species that is associated with beetles and is used as a model system in evolutionary biology. With 169 Mb and 23,500 predicted protein-coding genes, the P. pacificus genome is larger than those of Caenorhabditis elegans and the human parasite Brugia malayi. Compared to C. elegans, the P. pacificus genome has more genes encoding cytochrome P450 enzymes, glucosyltransferases, sulfotransferases and ABC transporters, many of which were experimentally validated. The P. pacificus genome contains genes encoding cellulase and diapausin, and cellulase activity is found in P. pacificus secretions, indicating that cellulases can be found in nematodes beyond plant parasites. The relatively higher number of detoxification and degradation enzymes in P. pacificus is consistent with its necromenic lifestyle and might represent a preadaptation for parasitism. Thus, comparative genomics analysis of three ecologically distinct nematodes offers a unique opportunity to investigate the association between genome structure and lifestyle.     

Mate sampling in a natural population of Pecos gambusia, Gambusia nobilis

Normal 0 false false false MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;} Much research has been conducted on the mating systems of poeciliid fish in aquaria; however, there are fewer studies that examine mate sampling of these fish in the wild. In general, male poeciliids are characterized as being unselective in their mate choices and will attempt to copulate with seemingly all available females. Females are selective, copulate infrequently, and are often pursued by “ardent” males who may force copulations. To avoid male harassment, females in aquaria will often shelter from males among other females in shoals. Here, we examined the mate-sampling behaviors of male and female Pecos gambusia Gambusia nobilis by following individuals swimming in an outflow pool of Diamond Y Spring in southwestern Texas. In most cases, a male approached a solitary female, followed her briefly, and then left for no apparent reason. Approaching a number of females increased the likelihood that the male would follow one, and the longer a male followed a female, the more likely he was to copulate with her. As females were larger and faster than males, they could avoid males by swimming away from them. We found no evidence of the persistent males that harass seemingly unreceptive females as seen under aquarium conditions, nor did we see females join a shoal to stop pursuit by males. However, the activity of one male following a female did appear to attract other males who would compete to follow and attempt copulation. This competition might ensure that only superior males gain reproductive opportunities. Se han investigado extensamente los sistemas de apareamiento de pecílidos en acuario; no obstante, hay relativamente pocos estudios que examinan la elección de pareja de estos peces en su hábitat natural. Los pecílidos machos no suelen ser selectivos en su elección de pareja y parecen intentar copular con todas las hembras que estén a su alcance. Las hembras son selectivas, no copulan frecuentemente y a menudo las persiguen machos excitados que pueden copular con ellas forzadamente. Para evitar el acosamiento de los machos, en acuario las hembras a menudo se refugian de los machos entre otras hembras en bancos. Para este estudio, examinamos el comportamiento de elección de pareja de gambusias de pecos ( Gambusia nobilis ) machos y hembras al observar algunos individuos en un remanso del Diamond Y Spring en el suroeste de Texas. En la mayoría de los casos, el macho se acercaba a una hembra solitaria, la seguía brevemente y luego se alejaba sin motivo aparente. El acercarse a varias hembras aumentaba la probabilidad de que persiguiera a una de ellas, y cuanto más la seguía, más probable era que copulara con ella. Dado que las hembras son más grandes y más rápidas que los machos, podían eludirlos si no correspondían. No observamos machos persistentes que acosaran hembras aparentemente poco receptivas como se ha documentado en acuario, ni tampoco vimos hembras que se unieran a bancos para evitar la persecución de machos. Pero cuando un macho perseguía una hembra, parecía atraer otros, los cuales competían entre sí para seguirla e intentar copular con ella. Esta competencia podría garantizar que solo los machos superiores tengan oportunidades reproductivas.