Phosphorylation and regulation of a G protein–coupled receptor by protein kinase CK2

We demonstrate a role for protein kinase casein kinase 2 (CK2) in the phosphorylation and regulation of the M3-muscarinic receptor in transfected cells and cerebellar granule neurons. On agonist occupation, specific subsets of receptor phosphoacceptor sites (which include the SASSDEED motif in the third intracellular loop) are phosphorylated by CK2. Receptor phosphorylation mediated by CK2 specifically regulates receptor coupling to the Jun-kinase pathway. Importantly, other phosphorylation-dependent receptor processes are regulated by kinases distinct from CK2. We conclude that G protein–coupled receptors (GPCRs) can be phosphorylated in an agonist-dependent fashion by protein kinases from a diverse range of kinase families, not just the GPCR kinases, and that receptor phosphorylation by a defined kinase determines a specific signalling outcome. Furthermore, we demonstrate that the M3-muscarinic receptor can be differentially phosphorylated in different cell types, indicating that phosphorylation is a flexible regulatory process where the sites that are phosphorylated, and hence the signalling outcome, are dependent on the cell type in which the receptor is expressed

Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code.

G-protein-coupled receptors are hyper-phosphorylated in a process that controls receptor coupling to downstream signaling pathways. The pattern of receptor phosphorylation has been proposed to generate a "bar code" that can be varied in a tissue-specific manner to direct physiologically relevant receptor signaling. If such a mechanism existed, receptors would be expected to be phosphorylated in a cell/tissue-specific manner. Using tryptic phosphopeptide maps, mass spectrometry, and phospho-specific antibodies, it was determined here that the prototypical G(q/11)-coupled M(3)-muscarinic receptor was indeed differentially phosphorylated in various cell and tissue types supporting a role for differential receptor phosphorylation in directing tissue-specific signaling. Furthermore, the phosphorylation profile of the M(3)-muscarinic receptor was also dependent on the stimulus. Full and partial agonists to the M(3)-muscarinic receptor were observed to direct phosphorylation preferentially to specific sites. This hitherto unappreciated property of ligands raises the possibility that one mechanism underlying ligand bias/functional selectivity, a process where ligands direct receptors to preferred signaling pathways, may be centered on the capacity of ligands to promote receptor phosphorylation at specific sites

Síntese e avaliação catalítica de catalisadores microporoso, mesoporosos e micro-mesoporosos

As propriedades e potencialidades dos materiais porosos estão em constantes estudos e usos nas mais variadas áreas da ciência. Esses materiais são atribuídos em classes de acordo com o ordenamento dos seus blocos estruturantes. Suas propriedades estão intrinsecamente relacionadas pela sua capacidade de catalisar as reações químicas. Neste trabalho, catalisadores do tipo HAlZSM-12, HAlMCM-41, HAlMCM-48, AlSBA-15 (Si/Al= 25, 50, 75) e HAlZSM-12/HAlMCM-41, HAlZSM-12/HAlMCM-48, HAlZSM-12/AlSBA-15 foram sintetizados pelo método hidrotérmico, submetidas a processos de calcinação e troca iônica e caracterizados por difratometria de raios-X. No presente trabalho também avaliou-se o potencial catalítico dos catalisadores na pirólise catalítica do ácido oléico em escala de bancada usando a termogravimetria. _________________________________________________________________________________________ ABSTRACT: The properties and potential of porous materials are in constant studies and uses in various areas of science. These materials are attributed to classes according to their structural ordering of blocks. Their properties are intrinsically related by their ability to catalyze chemical reactions. In this study, catalysts of type HAlZSM-12, HAlMCM-41, HAlMCM-48, AlSBA-15 (Si/Al 25, 50, 75) and composites HAlZSM-12/HAlMCM-41, HAlZSM-12/HAlMCM-48, HAlZSM-12/AlSBA-15 were synthesized by hydrothermal method, subjected to calcination and ion exchange processes and characterized by X-ray diffraction. In this study also were evaluated the catalytic potential of catalysts in the catalytic pyrolysis of oleic acid in micro-scale tests using thermogravimetric (TG)

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead