The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates alpha1 adrenergic receptor-induced cardiomyocyte hypertrophy.

In response to various pathological stresses, the heart undergoes a pathological remodeling process that is associated with cardiomyocyte hypertrophy. Because cardiac hypertrophy can progress to heart failure, a major cause of lethality worldwide, the intracellular signaling pathways that control cardiomyocyte growth have been the subject of intensive investigation. It has been known for more than a decade that the small molecular weight GTPase RhoA is involved in the signaling pathways leading to cardiomyocyte hypertrophy. Although some of the hypertrophic pathways activated by RhoA have now been identified, the identity of the exchange factors that modulate its activity in cardiomyocytes is currently unknown. In this study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor activity, is critical for activating RhoA and transducing hypertrophic signals downstream of alpha1-adrenergic receptors (ARs). In particular, our results indicate that suppression of AKAP-Lbc expression by infecting rat neonatal ventricular cardiomyocytes with lentiviruses encoding AKAP-Lbc-specific short hairpin RNAs strongly reduces both alpha1-AR-mediated RhoA activation and hypertrophic responses. Interestingly, alpha1-ARs promote AKAP-Lbc activation via a pathway that requires the alpha subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as the first Rho-guanine nucleotide exchange factor (GEF) involved in the signaling pathways leading to cardiomyocytes hypertrophy.

An adult thymic stromal-cell suspension model for in vitro positive selection.

Presented here is a cell-suspension model for positive selection using thymocytes from alphabeta-TCR (H-2Db-restricted) transgenic mice specific to the lymphocytic choriomeningitis virus (LCMV) on a nonselecting MHC background (H-2d or TAP-1 -/-), cocultured with freshly isolated adult thymus stromal cells of the selecting MHC type. The thymic stromal cells alone induced positive selection of functional CD4- CD8+ cells whose kinetics and efficiency were enhanced by nominal peptide. Fibroblasts expressing the selecting MHC alone did not induce positive selection; however, together with nonselecting stroma and nominal peptide, there was inefficient positive. These results suggest multiple signaling in positive selection with selection events able to occur on multiple-cell types. The ease with which this model can be manipulated should greatly facilitate the resolution of the mechanisms of positive selection in normal and pathological states.

Identification and characterization of the Arabidopsis PHO1 gene involved in phosphate loading to the xylem.

The Arabidopsis mutant pho1 is deficient in the transfer of Pi from root epidermal and cortical cells to the xylem. The PHO1 gene was identified by a map-based cloning strategy. The N-terminal half of PHO1 is mainly hydrophilic, whereas the C-terminal half has six potential membrane-spanning domains. PHO1 shows no homology with any characterized solute transporter, including the family of H(+)-Pi cotransporters identified in plants and fungi. PHO1 shows highest homology with the Rcm1 mammalian receptor for xenotropic murine leukemia retroviruses and with the Saccharomyces cerevisiae Syg1 protein involved in the mating pheromone signal transduction pathway. PHO1 is expressed predominantly in the roots and is upregulated weakly under Pi stress. Studies with PHO1 promoter-beta-glucuronidase constructs reveal predominant expression of the PHO1 promoter in the stelar cells of the root and the lower part of the hypocotyl. There also is beta-glucuronidase staining of endodermal cells that are adjacent to the protoxylem vessels. The Arabidopsis genome contains 10 additional genes showing homology with PHO1. Thus, PHO1 defines a novel class of proteins involved in ion transport in plants.

T cell costimulation by the TNF ligand BAFF.

The TNF ligand family member BAFF (B cell activating factor belonging to the TNF family, also called Blys, TALL-1, zTNF-4, or THANK) is an important survival factor for B cells [corrected]. In this study, we show that BAFF is able to regulate T cell activation. rBAFF induced responses (thymidine incorporation and cytokine secretion) of T cells, suboptimally stimulated through their TCR. BAFF activity was observed on naive, as well as on effector/memory T cells (both CD4+ and CD8+ subsets), indicating that BAFF has a wide function on T cell responses. Analysis of the signal transduced by BAFF into T cells shows that BAFF has no obvious effect on T cell survival upon activation, but is able to deliver a complete costimulation signal into T cells. Indeed, BAFF is sufficient to induce IL-2 secretion and T cell division, when added to an anti-TCR stimulation. This highlights some differences in the BAFF signaling pathway in T and B cells. In conclusion, our results indicate that BAFF may play a role in the development of T cell responses, in addition to its role in B cell homeostasis.

Low density lipoprotein signaling and pancreatic beta cells protection

SummaryLow-density lipoproteins (LDLs) have an important physiological role in organism transporting cholesterol and other fatty substances to target tissues. However, elevated LDL levels in the blood are associated with the formation of arterial plaques and consequently atherosclerosis. It is therefore important to characterize the intracellular pathways induced upon LDL stimulation as they might be involved in the pathological properties of these lipoproteins. It has been previously found that LDL stimulation of mouse embryonic fibroblasts activates p38 mitogen activated protein kinases (MAPKs). This leads to cell spreading and increase in the wound healing capabilities of the cells. These two responses might occur within atherosclerotic plaques.The aim of this project is to reveal the missing links between LDL particle and activation of p38 MAPK kinase. As previously shown in our lab activation of p38 MAPK kinase by the LDL particles occur independently of classical LDL receptor (LDLR). In this study we have shown that scavenger receptor type Β class I (SR-BI) is responsible for the signal transduction from the LDLs to the p38 MAPK. We have also shown that Mitogen activated kinase kinases (MKKs) that can directly activate ρ 38 MAPK in these conditions are MKK3 and MKK6 but not MKK4. We have also tested some of the intermediate components of the pathway like Ras and PI3 kinase but found that they do not play a role.The data obtained in this study showed a part of molecular mechanism responsible for p38 MAPK activation and subsequent wound healing and can contribute to our knowledge on function of the fibroblasts in the development of the atherosclerotic plaques.Diabetes Mellitus is a condition caused by disordered metabolism of blood glucose level. It is one of the most commonly spread disease in the western world, with the incidence reaching 8% of population in United States. Two most common types of diabetes are type 1 and 2 that differs slightly in the mechanism of the development. However in the basis of both types lies the cell death of pancreatic beta cells. The aim of this work is to improve beta cells survival in different pathophysiological settings. This could be extrapolated to the conditions in which Diabetes develops in humans. We decided to use RasGAP- derived fragment Ν with its strong antiapoptotic effect in beta cells. In our lab we have demonstrated that in the mild stress conditions RasGAP can be cleaved by caspases at the position 455 producing two fragments, fragment Ν and fragment C. Fragment Ν exerts

Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation.

The cytokine macrophage migration inhibitory factor plays a central role in inflammation, cell proliferation and tumorigenesis. Moreover, macrophage migration inhibitory factor levels correlate with tumor aggressiveness and metastatic potential. Histone deacetylase inhibitors are potent antitumor agents recently introduced in the clinic. Therefore, we hypothesized that macrophage migration inhibitory factor would represent a target of histone deacetylase inhibitors. Confirming our hypothesis, we report that histone deacetylase inhibitors of various chemical classes strongly inhibited macrophage migration inhibitory factor expression in a broad range of cell lines, in primary cells and in vivo. Nuclear run on, transient transfection with macrophage migration inhibitory factor promoter reporter constructs and transduction with macrophage migration inhibitory factor expressing adenovirus demonstrated that trichostatin A (a prototypical histone deacetylase inhibitor) inhibited endogenous, but not episomal, MIF gene transcription. Interestingly, trichostatin A induced a local and specific deacetylation of macrophage migration inhibitory factor promoter-associated H3 and H4 histones which did not affect chromatin accessibility but was associated with an impaired recruitment of RNA polymerase II and Sp1 and CREB transcription factors required for basal MIF gene transcription. Altogether, this study describes a new molecular mechanism by which histone deacetylase inhibitors inhibit MIF gene expression, and suggests that macrophage migration inhibitory factor inhibition by histone deacetylase inhibitors may contribute to the antitumorigenic effects of histone deacetylase inhibitors.

Hierarchical management of carbon sources is regulated similarly by the CbrA/B systems in Pseudomonas aeruginosa and Pseudomonas putida.

The CbrA/B system in pseudomonads is involved in the utilization of carbon sources and carbon catabolite repression (CCR) through the activation of the small RNAs crcZ in Pseudomonas aeruginosa, and crcZ and crcY in Pseudomonas putida. Interestingly, previous works reported that the CbrA/B system activity in P. aeruginosa PAO1 and P. putida KT2442 responded differently to the presence of different carbon sources, thus raising the question of the exact nature of the signal(s) detected by CbrA. Here, we demonstrated that the CbrA/B/CrcZ(Y) signal transduction pathway is similarly activated in the two Pseudomonas species. We show that the CbrA sensor kinase is fully interchangeable between the two species and, moreover, responds similarly to the presence of different carbon sources. In addition, a metabolomics analysis supported the hypothesis that CCR responds to the internal energy status of the cell, as the internal carbon/nitrogen ratio seems to determine CCR and non-CCR conditions. The strong difference found in the 2-oxoglutarate/glutamine ratio between CCR and non-CCR conditions points to the close relationship between carbon and nitrogen availability, or the relationship between the CbrA/B and NtrB/C systems, suggesting that both regulatory systems sense the same sort or interrelated signal.

A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.

PURPOSE: To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU). METHODS: EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues. RESULTS: After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13. CONCLUSIONS: This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.

n-3 PUFAs modulate T-cell activation via protein kinase C-alpha and -epsilon and the NF-kappaB signaling pathway.

We elucidated the mechanisms of action of two n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in Jurkat T-cells. Both DHA and EPA were principally incorporated into phospholipids in the following order: phosphatidylcholine < phosphatidylethanolamine < phosphatidylinositol/phosphatidylserine. Furthermore, two isoforms of phospholipase A(2) (i.e., calcium-dependent and calcium-independent) were implicated in the release of DHA and EPA, respectively, during activation of these cells. The two fatty acids inhibited the phorbol 12-myristate 13-acetate (PMA)-induced plasma membrane translocation of protein kinase C (PKC)-alpha and -epsilon. The two n-3 PUFAs also inhibited the nuclear translocation of nuclear factor kappaB (NF-kappaB) and the transcription of the interleukin-2 (IL-2) gene in PMA-activated Jurkat T-cells. Together, these results demonstrate that DHA and EPA, being released by two isoforms of phospholipase A(2), modulate IL-2 gene expression by exerting their action on two PKC isoforms and NF-kappaB in Jurkat T-cells.

Sibling rivalry and vocal negotiation in the barn owl Tyto alba

Chez les animaux, les jeunes dépendant des parents durant leur développement sont en compétition pour obtenir la nourriture, qu'ils quémandent par des cris et postures ostentatoires et se disputent physiquement. Les frères et soeurs n'ont pas la même compétitivité, en particulier s'ils diffèrent en âge, et leur niveau de faim fluctue dans le temps. Comme dans tout type de compétition, chacun doit ajuster son investissement aux rivaux, c'est à dire aux besoins et comportements de ses frères et soeurs. Dans le contexte de la famille, selon la théorie de sélection de parentèle, les jeunes bénéficient de leur survie mutuelle et donc de la propagation de la part de gènes qu'ils ont en commun. L'hypothèse de la « négociation frères-soeurs » prédit que, sous certaines conditions, les jeunes négocient entre eux la nourriture, ce qui réduit les coûts de compétition et permet de favoriser les frères et soeurs les plus affamés. La littérature actuelle se focalise sur les signaux de quémande entre enfants et parents et les interactions compétitives frères-soeurs sont étudiées principalement au sein de paires, alors que les nichées ou portées en comprennent souvent de nombreux. Cette thèse vise à mieux comprendre comment et jusqu'à quel point plusieurs jeunes ajustent mutuellement leurs signaux de besoin. C'est une question importante, étant donné que cela influence la répartition de nourriture entre eux, donc la résolution du conflit qui les oppose et à terme leur valeur évolutive. Le modèle d'étude est la chouette effraie (Tyto alba), chez laquelle jusqu'à neufs poussins émettent des milliers de cris chacun par nuit. Ils négocieraient entre eux la prochaine proie indivisible rapportée au nid avant que les parents ne reviennent : un poussin affamé crie plus qu'un autre moins affamé, ce qui dissuade ce dernier de crier en retour et par la suite de quémander la nourriture aux parents. L'investissement optimal correspondrait donc à écarter son frère en permanence vu que l'arrivée des parents est imprévisible, mais à moindre coût. Dans un premier axe, nous avons exploré au sein de dyades les mécanismes acoustiques permettant aux poussins de doser leur effort vocal durant les heures de compétition où ils sont laissés seuls au nid. Nous avons trouvé que les poussins évitent de crier simultanément, ce qui optimiserait la discrimination du nombre et de la durée de leurs cris, lesquels reflètent de façon honnête leur niveau de faim et donc leur motivation. L'alternance des cris paraît particulièrement adaptée au fait que les poussins se fient à des variations temporelles subtiles dans le rythme et la durée de leurs vocalisations pour prendre la parole. En particulier, allonger ses cris tout en criant moins dissuade efficacement le rival de répondre, ce qui permet de monopoliser la parole dans de longs « monologues ». Ces règles seraient universelles puisqu'elles ne dépendent pas de la séniorité, de la faim, ni de la parenté et les poussins répondent à un playback de façon similaire à un vrai frère. Tous ces résultats apportent la première preuve expérimentale que les juvéniles communiquent de façon honnête sur leurs besoins, ajustent activement le rythme de leurs cris et utilisent des composantes multiples de leurs vocalisations d'une façon qui réduit le coût de la compétition. De plus, il s'agit de la première démonstration que des règles de conversation régissent de longs échanges vocaux chez les animaux de façon comparable aux règles basiques observées chez l'Homme. Dans un second axe, nous avons exploré les stratégies comportementales que les poussins adoptent pour rivaliser avec plusieurs frères et soeurs, par le biais d'expériences de playback. Nous avons trouvé que les poussins mémorisent des asymétries de compétitivité entre deux individus qui dialoguent et répondent plus agressivement au moins compétitif une fois qu'ils sont confrontés à chacun isolément. Dans la même ligne, quand ils entendent un nombre variable d'individus criant à un taux variable, les poussins investissent le plus contre des rivaux moins nombreux et moins motivés. En accord avec les prédictions des modèles théoriques, les poussins de chouette effraie escaladent donc les conflits pour lesquels leur chance de gagner contrebalance le plus l'énergie dépensée. Nous révélons ainsi que 1) les jeunes frères et soeurs 'espionnent' les interactions de leurs rivaux pour évaluer leur compétitivité relative, ce qui est sans doute moins coûteux qu'une confrontation directe avec chacun, et 2) dosent leur investissement vocal en fonction du nombre de rivaux actuellement en compétition et de leur motivation de façon concomitante. Ces résultats montrent que les interactions entre frères et soeurs au nid reposent sur des mécanismes similaires à ceux observés, mais encore de façon anecdotique, chez les adultes non apparentés qui se disputent les territoires et partenaires sexuels. Cette thèse souligne donc combien il est crucial de considérer dorénavant la famille comme un réseau de communication à part entière pour mieux comprendre comment les jeunes résolvent les conflits autour du partage des ressources parentales. Plus généralement, elle révèle l'importance de la dynamique temporelle des vocalisations dans les conflits et la communication des animaux. A la lumière de nos résultats, la chouette effraie apparaît comme un modèle clé pour de futures recherches sur la résolution des conflits et la communication acoustique. - In species with parental care, offspring contest priority access to food by begging through conspicuous postures and vocalisations and by physically jockeying. Siblings differ in their competitiveness, especially in the case of age and size hierarchies, and their hunger level fluctuates in time. As in competition in general, each individual should adjust its investment to opponents that is to say to its siblings' needs and behaviours. In the particular context of family, according to kin selection theory, siblings derive extra fitness benefits from their mutual survival and hence the spreading of the genes they share. The "sibling negotiation" predicts that, under certain conditions, young would negotiate among them priority access to food, which reduces competition costs and enables promoting the most hungry siblings. To date, the literature focuses on signals of need between parents and offspring and competitive interactions (in particular among siblings) are mostly studied within pairwise interactions, yet they commonly involve more numerous rivals. This PhD aims at better understanding how and the extent to which several young siblings compete through signalling. This is important since this influences how food is allocated among them, thus the outcome of sibling rivalry and ultimately their fitness. I use the barn owl (Tyto alba) as a model, in which the one to nine nestlings emit a simple noisy call thousands of times per night. Thereby, they would negotiate among them priority access to the indivisible food next delivered prior to parents' feeding visits. A hungry nestling emits more calls than a less hungry sibling, which deters it to call in return and ultimately beg food at parents. The optimal investment thus corresponds to constantly deterring the rival to compete, given that parents' arrival is unpredictable, but at the lowest costs. In the first axis of my thesis, we explored within dyads the acoustic mechanisms by which owlets dose vocal effort when competing during the hours they are left alone. We found that owlets avoid overlapping each other's calls. This would enhance the discrimination of both call number and duration, which honestly reflect individuals' hunger level and hence motivation to compete. Such antiphony seems best adapted to the fact that siblings actually use subtle temporal variations in the rhythm and duration of their calls to take or give their turn. Owlets alternate monologs, in which lengthening calls efficiently deters the rival to respond while reducing call number. Such rules depend neither on seniority, hunger level nor kinship since nestlings responded similarly to a live sibling and an unrelated playback individual. Taken together, these findings provide the first experimental proof that dependent young honestly communicate about their need, actively adjust the timing of their calls and use multicomponent signals in a way that reduces vocal costs. Moreover, this is the first demonstration of conversational rules underlying animal long-lasting vocal exchanges comparable to the basic turn-taking signals observed in humans. In the second axis, we focused on the behavioural strategies owlets adopt to compete with more than one sibling, using playback experiments. We found that singleton bystanders memorised competitive asymmetries between two playback individuals dialoguing and responded more aggressively to the submissive one once they later faced each of both alone. Moreover, when hearing a varying number of nestlings calling at varying rates, owlets vocally invested the most towards fewer and less motivated rivals. In line with predictions from models on conflict settlement, barn owls thus escalate contests in which their chance of winning best counterbalances the energy spent. These results reveal that young socially eavesdrop on their siblings' interactions to assess their relative competitiveness at likely lower costs than direct confrontation, and dose vocal effort relative to both their number and motivation. This shows that young siblings' interactions imply mechanisms similar to those observed, yet still anecdotally, in unrelated adults that contest mates and territories. This PhD therefore highlights how crucial it is to further consider family as a communication network to better understand how siblings resolve conflicts over the share of parental resources. More generally, it provides important insights into the role of the temporal dynamics of signalling during animal contests and communication. In the light of our findings, the barn owl emerges as a key model for future research on conflict resolution and acoustic communication in animals.

TCR-induced NF-kappaB activation: a crucial role for Carma1, Bcl10 and MALT1.

T-cell receptor (TCR) engagement induces the maturation of thymocytes and the activation and proliferation of peripheral T cells through signaling pathways that target several transcription factors. The transcription factor nuclear factor-κB (NF-κB) has an essential role in the activation of mature T cells but the signaling pathway leading from TCR stimulation to NF-κB activation is not well defined. Carma1, Bcl10 and MALT1 are recently identified proteins that have an important and previously unexpected role in antigen receptor-induced NF-κB activation and the control of lymphocyte proliferation. We believe that the recent advances in this field could stimulate research for the development of new immunomodulatory drugs and could lead to a better understanding of the molecular mechanisms underlying the formation of lymphomas and potentially of other immune disorders.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning.

DP1, a dimerization partner protein of the transcription factor E2F, is known to inhibit Wnt/β-catenin signalling along with E2F, although the function of DP1 itself was not well characterized. Here, we present a novel dual regulatory mechanism of Wnt/β-catenin signalling by DP1 independent from E2F. DP1 negatively regulates Wnt/β-catenin signalling by inhibiting Dvl-Axin interaction and by enhancing poly-ubiquitination of β-catenin. In contrast, DP1 positively modulates the signalling upon Wnt stimulation, via increasing cytosolic β-catenin and antagonizing the kinase activity of NLK. In Xenopus embryos, DP1 exerts both positive and negative roles in Wnt/β-catenin signalling during anteroposterior neural patterning. From subcellular localization analyses, we suggest that the dual roles of DP1 in Wnt/β-catenin signalling are endowed by differential nucleocytoplasmic localizations. We propose that these dual functions of DP1 can promote and stabilize biphasic Wnt-on and Wnt-off states in response to a gradual gradient of Wnt/β-catenin signalling to determine differential cell fates.

Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin

The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either beta-catenin or gamma-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of beta- and gamma-catenin. Double-deficient hematopoietic stem cells maintain long-term repopulation capacity and multilineage differentiation potential. Unexpectedly, 2 independent ex vivo reporter gene assays show that Wnt signal transmission is maintained in double-deficient hematopoietic stem cells, thymocytes, or peripheral T cells. In contrast, Wnt signaling is strongly reduced in thymocytes lacking TCF-1 or in nonhematopoietic cells devoid of beta-catenin. These data provide the first evidence that hematopoietic cells can transduce canonical Wnt signals in the combined absence of beta- and gamma-catenin

Ferripyochelin uptake genes are involved in pyochelin-mediated signalling in Pseudomonas aeruginosa.

In response to iron starvation, Pseudomonas aeruginosa produces the siderophore pyochelin. When secreted to the extracellular environment, pyochelin chelates iron and transports it to the bacterial cytoplasm via its specific outer-membrane receptor FptA and the inner-membrane permease FptX. Exogenously added pyochelin also acts as a signal which induces the expression of the pyochelin biosynthesis and uptake genes by activating PchR, a cytoplasmic regulatory protein of the AraC/XylS family. The importance of ferripyochelin uptake genes in this regulation was evaluated. The fptA and fptX genes were shown to be part of the fptABCX ferripyochelin transport operon, which is conserved in Burkholderia sp. and Rhodospirillum rubrum. The fptB and fptC genes were found to be dispensable for utilization of pyochelin as an iron source, for signalling and for pyochelin production. By contrast, mutations in fptA and fptX not only interfered with pyochelin utilization, but also affected signalling and diminished siderophore production. It is concluded from this that pyochelin-mediated signalling operates to a large extent via the ferripyochelin transport system.