Electrophilic fatty acid species inhibit 5-lipoxygenase and attenuate sepsis-induced pulmonary inflammation.

Aims: The reaction of nitric oxide and nitrite-derived species with polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene derivatives (NO2-FA), which display anti-inflammatory properties. Given that the 5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which are potentially sensitive to electrophilic modifications, we determined the consequences of NO2-FA on 5-LO activity in vitro and on 5-LO-mediated inflammation in vivo.

Results: Stimulation of human polymorphonuclear leukocytes (PMNL) with nitro-oleic (NO2-OA) or nitro-linoleic acid (NO2-LA) (but not the parent lipids) resulted in the concentration-dependent and irreversible inhibition of 5-LO activity.

The peptide transporter PEPT1 is expressed in distal colon in rodents and humans and contributes to water absorption.

The peptide transporter PEPT1, expressed in the brush border membrane of enterocytes, mediates the uptake of di- and tripeptides from luminal protein digestion in the small intestine. PEPT1 was proposed not to be expressed in normal colonic mucosa but may become detectable in inflammatory states such as Crohn's disease or ulcerative colitis. We reassessed colonic expression of PEPT1 by performing a systematic analysis of PEPT1 mRNA and protein levels in healthy colonic tissues in mice, rats, and humans.

Where EGF receptors transmit their signals.

Excessive signaling by receptor tyrosine kinases (RTKs) can cause cancer. What molecular mechanisms normally control RTK signaling? Are they defective in tumors? If so, should therapeutics be developed to restore particular regulatory pathways to cancer cells? These questions have been approached through mechanistic studies of a prototypical RTK, the epidermal growth factor receptor (EGFR). EGFR signaling is mediated and regulated by both signaling and trafficking effectors.

A novel biotinylated lipid raft reporter for electron microscopic imaging of plasma membrane microdomains.

The submicroscopic spatial organization of cell surface receptors and plasma membrane signaling molecules is readily characterized by electron microscopy (EM) via immunogold labeling of plasma membrane sheets. Although various signaling molecules have been seen to segregate within plasma membrane microdomains, the biochemical identity of these microdomains and the factors affecting their formation are largely unknown. Lipid rafts are envisioned as submicron membrane subdomains of liquid ordered structure with differing lipid and protein constituents that define their specific varieties.

Cbl controls EGFR fate by regulating early endosome fusion.

Amino acid residues 1 to 434 of the E3 ubiquitin ligase Cbl control signaling of the epidermal growth factor receptor (EGFR) by enhancing its ubiquitination, down-regulation, and lysosomal degradation. This region of Cbl comprises a tyrosine kinase-binding domain, a linker region, a really interesting new gene finger (RF), and a subset of the residues of the RF tail. In experiments with full-length alanine substitution mutants, we demonstrated that the RF tail of Cbl regulated biochemically distinct checkpoints in the endocytosis of EGFR.