Receptor tyrosine kinases (RTKs) direct diverse cellular and developmental responses by stimulating a relatively small number of overlapping signaling pathways. Specificity may be determined by RTK expression patterns or by differential activation of individual signaling pathways. To address this issue we generated knock-in mice in which the extracellular domain of the mouse platelet-derived growth factor alpha receptor (PDGF␣R) is fused to the cytosolic domain of Drosophila Torso (␣ Tor ) or the mouse fibroblast growth factor receptor 1 (␣ FR ). ␣ Tor homozygous embryos exhibit significant rescue of neural crest and angiogenesis defects normally found in PDGF␣R-null embryos yet fail to rescue skeletal or extraembryonic defects. This phenotype was associated with the ability of ␣ Tor to stimulate the mitogen-activated protein (MAP) kinase pathway to near wildtype levels but failure to completely activate other pathways, such as phosphatidylinositol (PI) 3-kinase. The ␣ FR chimeric receptor fails to rescue any aspect of the PDGF␣R-null phenotype. Instead, ␣ FR expression leads to a gain-of-function phenotype highlighted by ectopic bone development. The ␣ FR phenotype was associated with a failure to limit MAP kinase signaling and to engage significant PI3-kinase response. These results suggest that precise regulation of divergent downstream signaling pathways is critical for specification of RTK function.Evolutionary conservation of a gene requires that it contributes specific functions that enhance the fitness of the organism in which it is expressed. Receptor tyrosine kinases (RTKs) represent a large family of genes that have been conserved due to their ability to control multiple fundamental cellular processes. Upon binding to specific extracellular ligands, activated RTKs regulate cell proliferation, survival, migration, differentiation, and metabolism. The conservation of over 50 RTKs in mammals suggests that each executes critical specific cellular functions. How functional specificity is generated remains a matter of controversy. A vast amount of research has focused on understanding the molecular mechanisms that underlie the ability of these receptors to mediate diverse cellular functions. Surprisingly, studies have shown that even divergent RTKs activate highly redundant array of downstream signaling proteins, such as mitogen-activated protein (MAP) kinases, Src family kinases, phospholipase C (PLC)-␥, and phosphatidylinositol (PI) 3-kinase. Several models have been proposed to explain how RTKs achieve functional specificity at the cellular level while at the molecular level appearing to activate redundant signaling pathways (12,27).One model proposes that specific responses to RTKs are a result of differential activation of downstream pathways or biochemical differences in RTK signaling. A great deal of evidence based on experiments performed in cultured cell lines to assess individual contributions of downstream signaling pathways supports this idea (14,26). Differences in the strength and/or duration ...

A central issue in signal transduction is the physiological contribution of different growth factor-initiated signaling pathways. We have generated knockin mice harboring mutations in the PDGFalpha receptor (PDGFalphaR) that selectively eliminate its capacity to activate PI3 kinase (alpha(PI3K)) or Src family kinases (alpha(Src)). The alpha(PI3K) mutation leads to neonatal lethality due to impaired signaling in many cell types, but the alpha(Src) mutation only affects oligodendrocyte development. A third knockin line containing mutations that eliminate multiple docking sites does not increase the severity of the alpha(PI3K) mutation. However, embryos with mutations in the PI3K binding sites of both PDGFRs (alpha and beta) recapitulate the PDGFalphaR null phenotype. Our results indicate that PI3K has a predominant role in PDGFalphaR signaling in vivo and that RTK-activated signaling pathways execute both specific and overlapping functions during mammalian development.

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Background: The role of non-medical prescribers working in palliative care has been expanding in recent years and prescribers report improvements in patient care, patient safety, better use of health professionals' skills and more flexible team working. Despite this, there is a lack of empirical evidence to demonstrate its clinical and economic impact, limiting our understanding of the future role of non-medical prescribers within a healthcare system serving an increasing number of people with palliative care needs. Aim: We developed a unique methodology to establish the level of non-medical prescribers' activity in palliative care across England and consider the likely overall contribution these prescribers are making at a national level in this context in relation to medical prescribing. Setting/participants: All prescriptions for 10 core palliative care drugs prescribed by general practitioners, nurses and pharmacists in England and dispensed in the community between April 2011 and April 2015 were extracted from the Prescribing Analysis Cost Tool system. Design: The data were broken down by prescriber and basic descriptive analysis of prescription frequencies by opioid, non-opioids and total prescriptions by year were undertaken. To evaluate the yearly growth of non-medical prescribers, the total number of prescriptions was compared by year for each prescribing group. Results: Non-medical prescribers issued prescriptions rose by 28% per year compared to 9% in those issued by medical prescribers. Despite this, the annual growth in non-medical prescribers prescriptions was less than 1% a year in relation to total community palliative care prescribing activity in England. Impact on medical prescribing is therefore minimal.