High- and Low-Affinity Epidermal Growth Factor Receptor-Ligand Interactions Activate Distinct Signaling Pathways

Signaling mediated by the Epidermal Growth Factor Receptor (EGFR) is crucial in normal development, and aberrant EGFR signaling has been implicated in a wide variety of cancers. Here we find that the high- and low-affinity interactions between EGFR and its ligands activate different signaling pathways. While high-affinity ligand binding is sufficient for activation of most canonical signaling pathways, low-affinity binding is required for the activation of the Signal transducers and activators of transcription (Stats) and Phospholipase C-gamma 1 (PLCγ1). As the Stat proteins are involved in many cellular responses including proliferation, migration and apoptosis, these results assign a function to low-affinity interactions that has been omitted from computational models of EGFR signaling. The existence of receptors with distinct signaling properties provides a way for EGFR to respond to different concentrations of the same ligand in qualitatively different ways

Conserved expression and functions of PDE4 in rodent and human heart

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts

Food site residence time and female competitive relationships in wild gray-cheeked mangabeys (Lophocebus albigena)

Authors of socioecological models propose that food distribution affects female social relationships in that clumped food resources, such as fruit, result in strong dominance hierarchies and favor coalition formation with female relatives. A number of Old World monkey species have been used to test predictions of the socioecological models. However, arboreal forest-living Old World monkeys have been understudied in this regard, and it is legitimate to ask whether predominantly arboreal primates living in tropical forests exhibit similar or different patterns of behavior. Therefore, the goal of our study was to investigate female dominance relationships in relation to food in gray-cheeked mangabeys (Lophocebus albigena). Since gray-cheeked mangabeys are largely frugivorous, we predicted that females would have linear dominance hierarchies and form coalitions. In addition, recent studies suggest that long food site residence time is another important factor in eliciting competitive interactions. Therefore, we also predicted that when foods had long site residence times, higher-ranking females would be able to spend longer at the resource than lower-ranking females. Analyses showed that coalitions were rare relative to some other Old World primate species, but females had linear dominance hierarchies. We found that, contrary to expectation, fruit was not associated with more agonism and did not involve long site residence times. However, bark, a food with a long site residence time and potentially high resource value, was associated with more agonism, and higher-ranking females were able to spend more time feeding on it than lower-ranking females. These results suggest that higher-ranking females may benefit from higher food and energy intake rates when food site residence times are long. These findings also add to accumulating evidence that food site residence time is a behavioral contributor to female dominance hierarchies in group-living species