Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis

Background Cyclin-dependent protein kinase-5 (CDK5) is an unusual member of the CDK family as it is not cell cycle regulated. However many of its substrates have roles in cell growth and oncogenesis, raising the possibility that CDK5 modulation could have therapeutic benefit. In order to establish whether changes in CDK5 activity are associated with oncogenesis one could quantify phosphorylation of CDK5 targets in disease tissue in comparison to appropriate controls. However the identity of physiological and pathophysiological CDK5 substrates remains the subject of debate, making the choice of CDK5 activity biomarkers difficult. Methods Here we use in vitro and in cell phosphorylation assays to identify novel features of CDK5 target sequence determinants that confer enhanced CDK5 selectivity, providing means to select substrate biomarkers of CDK5 activity with more confidence. We then characterize tools for the best CDK5 substrate we identified to monitor its phosphorylation in human tissue and use these to interrogate human tumour arrays. Results The close proximity of Arg/Lys amino acids and a proline two residues N-terminal to the phosphorylated residue both improve recognition of the substrate by CDK5. In contrast the presence of a proline two residues C-terminal to the target residue dramatically reduces phosphorylation rate. Serine-522 of Collapsin Response Mediator-2 (CRMP2) is a validated CDK5 substrate with many of these structural criteria. We generate and characterise phosphospecific antibodies to Ser522 and show that phosphorylation appears in human tumours (lung, breast, and lymphoma) in stark contrast to surrounding non-neoplastic tissue. In lung cancer the anti-phospho-Ser522 signal is positive in squamous cell carcinoma more frequently than adenocarcinoma. Finally we demonstrate that it is a specific and unusual splice variant of CRMP2 (CRMP2A) that is phosphorylated in tumour cells. Conclusions For the first time this data associates altered CDK5 substrate phosphorylation with oncogenesis in some but not all tumour types, implicating altered CDK5 activity in aspects of pathogenesis. These data identify a novel oncogenic mechanism where CDK5 activation induces CRMP2A phosphorylation in the nuclei of tumour cells

Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages

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La grotte des Planches-près-Arbois (Jura)

Barbier Aline, Boudin R.-C., Chaix Louis, Délibrias Georgette, Erroux J., Lundström-Baudais Karen, Passard Françoise, Pétrequin Anne-Marie, Petrequin Pierre, Picard P., Piningre J F, Rutkowski H., Urlacher J. P., Séné G., Vuaillat Dominique. La grotte des Planches-près-Arbois (Jura). In: Gallia préhistoire, tome 24, fascicule 1, 1981. pp. 145-200

Guidelines for social life cycle assessment of products and organizations

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High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation.

Collapsin Response Mediator Protein (CRMP)-2 is involved in T-cell polarization and migration. To address the role of CRMP2 in neuroinflammation, we analyzed its involvement in lymphocyte recruitment to the central nervous system in mouse infected with neurotropic and non-neurotropic virus strains (RABV, CDV). A sub-population of early-activated CD69+CD3+ T lymphocytes highly expressing CRMP2 (CRMP2hi) peaked in the blood, lymph nodes and brain of mice infected with neurotropic viruses, and correlated with severity of disease. They displayed high migratory properties reduced by CRMP2 blocking antibody. These data point out the potential use of CRMP2 as a peripheral indicator of neuroinflammation

Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN

We demonstrate that the key target of increased PIP3 on cell polarity and migration is the excessive Akt signaling. In Dictyostelium, the defects in cells lacking PTEN are suppressed by the secondary deletions of PkbA, or its activator, TorC2. Multiple novel PkbA substrates are identified, and one of them, PakA, links PIP3 to downstream signaling