The p85␣ regulatory subunit of class I A phosphoinositide 3-kinases (PI3K) is derived from the Pik3r1 gene, which also yields alternatively spliced variants p50␣ and p55␣. It has been proposed that excess monomeric p85 competes with functional PI3K p85-p110 heterodimers. We examined embryonic stem (ES) cells with heterozygous and homozygous disruptions in the Pik3r gene and found that wild type ES cells express virtually no monomeric p85␣. Although, IGF-1-stimulated PI3K activity associated with insulin receptor substrates was unaltered in all cell lines, p85␣-null ES cells showed diminished protein kinase B activation despite increased PI3K activity associated with the p85 subunit. Furthermore, p85␣-null cells demonstrated growth retardation, increased frequency of apoptosis, and altered cell cycle regulation with a G 0 /G 1 cell cycle arrest and up-regulation of p27 KIP , whereas signaling through CREB and MAPK was enhanced. These phenotypes were reversed by re-expression of p85␣ via adenoviral gene transfer. Surprisingly, all ES cell lines could be differentiated into adipocytes. In these differentiated ES cells, however, compensatory p85 signaling was lost in p85␣-null cells while increased signaling by CREB and MAPK was still observed. Thus, loss of p85␣ in ES cells induced alterations in IGF-1 signaling and regulation of apoptosis and cell cycle but no defects in differentiation. However, differentiated ES cells partially lost their ability for compensatory signaling at the level of PI3K, which may explain some of the defects observed in mice with homozygous deletion of the Pik3r1 gene.Phosphoinositide 3-kinase (PI3K) 1 generates phosphorylated phosphoinositides (PI), which serve as crucial second messengers for a wide range of biological functions including mitogenesis, survival, differentiation, and cytoskeletal organization. PI3Ks are divided in three major classes according to substrate specificity, amino acid sequence, and homology of their lipid kinase domains. Class IA PI3K phosphorylates phosphatidylinositol (PtdIns), PtdIns 4-phosphate, and PtdIns 4,5-bisphosphate and are active as heterodimers consisting of regulatory and catalytic subunits. Activation of class 1A PI3K occurs by receptor-tyrosine kinases like the insulin-like growth factor-1 (IGF-1) receptor either by direct binding to tyrosine-phosphorylated pYMXM and pYXXM motifs of the IGF-1 receptor -chain and insulin receptor substrates (IRS) (1-4).There are multiple regulatory and catalytic subunits of class 1A PI3K. These regulatory subunits are derived from three different genes and can be classified according to their molecular structure. The full-length regulatory subunits are derived from distinct genes, the Pik3r1 (p85␣) and Pikr2 (p85) genes and are comprised of an NH 2 -terminal SH3 domain and a BCR homology region flanked by two proline-rich sites (1-4). In addition, the Pik3r1 gene yields smaller splicing variants of p55kDa (p55␣; also called AS53) and 50 kDa (p50␣) (5-7). Another short regulatory subunit is p55␥; this is stru...
User stories are popular for conveying requirements in agile software projects. Despite existing quality criteria, authors make formal mistakes that result in "bad" user story quality. If developers have insufficient experience in balancing quality problems, the creation of a shared mental model is impossible, thus increasing the risk of impacts on the project's success. This article provides a work-in-progress research model to set these variables in relation and establish a systematic method to uncover answers regarding their correlation. Details on the effects support research in agile requirements engineering to gain a better understanding of cognitive processes in the comprehension of user stories. In addition, insights can help to develop design recommendations and AI tools to improve user stories. A first evaluation of the model provides promising insights into the behavior and forms a basis for future research.
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