Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been implicated in signal transduction through tyrosine kinase-and heterotrimeric G-proteinlinked receptors. We report herein the cloning and characterization of p110␦, a novel class I PI3K. Like p110␣ and p110, other class I PI3Ks, p110␦ displays a broad phosphoinositide lipid substrate specificity and interacts with SH2͞SH3 domaincontaining p85 adaptor proteins and with GTP-bound Ras. In contrast to the widely distributed p110␣ and , p110␦ is exclusively found in leukocytes. In these cells, p110␣ and ␦ both associate with the p85␣ and  adaptor subunits and are similarly recruited to activated signaling complexes after treatment with the cytokines interleukin 3 and 4 and stem cell factor. Thus, these class I PI3Ks appear not to be distinguishable at the level of p85 adaptor selection or recruitment to activated receptor complexes. However, distinct biochemical and structural features of p110␦ suggest divergent functional͞regulatory capacities for this PI3K. Unlike p110␣, p110␦ does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity. In addition, the p110␦ catalytic domain contains unique potential proteinprotein interaction modules such as a Pro-rich region and a basic-region leucine-zipper (bZIP)-like domain. Possible selective functions of p110␦ in white blood cells are discussed.Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3Ј OH position of the inositol ring of inositol lipids, generating phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate. PI3K enzymes have been identified in plants, slime molds, yeast, fruit flies, and mammals (1) and play a role in signal transduction via tyrosine kinase-and G-protein-linked receptors (2-5). In addition, PI3Ks have a function in membrane trafficking events, either constitutive or induced upon receptor stimulation (for review, see ref. 6).
Fatty aldehyde dehydrogenase (FALDH, ALDH3A2) is thought to be involved in the degradation of phytanic acid, a saturated branched chain fatty acid derived from chlorophyll. However, the identity, subcellular distribution, and physiological roles of FALDH are unclear because several variants produced by alternative splicing are present in varying amounts at different subcellular locations. Subcellular fractionation experiments do not provide a clear-cut conclusion because of the incomplete separation of organelles. We established human cell lines heterologously expressing mouse FALDH from each cDNA without tagging under the control of an inducible promoter and detected the variant FALDH proteins using a mouse FALDHspecific antibody. One variant, FALDH-V, was exclusively detected in peroxisomal membranes. Human FALDH-V with an amino-terminal Myc sequence also localized to peroxisomes. The most dominant form, FALDH-N, and other variants examined, however, were distributed in the endoplasmic reticulum. A gas chromatography-mass spectrometry-based analysis of metabolites in FALDH-expressing cells incubated with phytol or phytanic acid showed that FALDH-V, not FALDH-N, is the key aldehyde dehydrogenase in the degradation pathway and that it protects peroxisomes from oxidative stress. In contrast, both FALDHs had a protective effect against oxidative stress induced by a model aldehyde for lipid peroxidation, dodecanal. These results suggest that FALDH variants are produced by alternative splicing and share an important role in protecting against oxidative stress in an organelle-specific manner.Plants produce a variety of secondary metabolites, and some of these are potentially toxic to animals (1). Herbivora have developed behavioral and physiological strategies to avoid specific plants and to detoxify any toxins ingested. Detoxification can occur in the mouth and the gut rumen with or without the help of microbes (2). The absorbed toxins must be detoxified in the intestine and liver, but studies on these mechanisms are limited because to date most animal experiments have been carried out using laboratory diets. Recently we found that a nuclear receptor, peroxisome proliferator-activated receptor ␣ (PPAR␣), 2 is involved in the detoxification by using plant seeds as a diet for mice (3).PPAR␣ is activated by fatty acid ligands and is an important regulator of lipid metabolism in animals (4). Despite the claimed essential role of this receptor in the liver, the PPAR␣-null mouse shows little phenotypic change when fed a normal laboratory diet (5, 6). We have examined its extrahepatic roles and found that PPAR␣ induces the expression of 17-hydroxysteroid dehydrogenase type 11 in the intestine (7). Recent studies on the substrates of 17-hydroxysteroid dehydrogenase type 11 showed that they include not only glucocorticoids and sex steroids but also bile acids, fatty acids, and branched amino acids (8, 9). So we examined the possibility that PPAR␣ plays a vital role in inducing enzymes for metabolizing secondary metabolites...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.