Sprouty2 and Spred1-2 Proteins Inhibit the Activation of the ERK Pathway Elicited by Cyclopentenone Prostanoids

Sprouty and Spred proteins have been widely implicated in the negative regulation of the fibroblast growth factor receptor-extracellular regulated kinase (ERK) pathway. In considering the functional role of these proteins, we explored their effects on ERK activation induced by cyclopentenone prostanoids, which bind to and activate Ras proteins. We therefore found that ectopic overexpression in HeLa cells of human Sprouty2, or human Spred1 or 2, inhibits ERK1/2 and Elk-1 activation triggered by the cyclopentenone prostanoids PGA1 and 15d-PGJ2. Furthermore, we found that in HT cells that do not express Sprouty2 due to hypermethylation of its gene-promoter, PGA1-provoked ERK activation was more intense and sustained compared to other hematopoietic cell lines with unaltered Sprouty2 expression. Cyclopentenone prostanoids did not induce Sprouty2 tyrosine phosphorylation, in agreement with its incapability to activate tyrosine-kinase receptors. However, Sprouty2 Y55F, which acts as a defective mutant upon tyrosine-kinase receptor stimulation, did not inhibit cyclopentenone prostanoids-elicited ERK pathway activation. In addition, Sprouty2 did not affect the Ras-GTP levels promoted by cyclopentenone prostanoids. These results unveil both common and differential features in the activation of Ras-dependent pathways by cyclopentenone prostanoids and growth factors. Moreover, they provide the first evidence that Sprouty and Spred proteins are negative regulators of the ERK/Elk-1 pathway activation induced not only by growth-factors, but also by reactive lipidic mediators

L'éthique, exigence professionnelle ou impératif social ; acteurs et chercheurs, deux mondes, deux morales ? Transparence et réserve ; éthique et esthétique

Boucher N., Burgel Guy, Cohen Jeanine, Coste Michel, Giu R., Maximy René de, Parent Michel, Querrien Anne, Robert M., Robin Christelle, Vieillard -Baron H. L'éthique, exigence professionnelle ou impératif social ; acteurs et chercheurs, deux mondes, deux morales ? Transparence et réserve ; éthique et esthétique. In: Villes en parallèle, n°17-18, avril 1991. Acteurs et chercheurs dans la ville. pp. 255-263

L'éthique, exigence professionnelle ou impératif social ; acteurs et chercheurs, deux mondes, deux morales ? Transparence et réserve ; éthique et esthétique

Boucher N., Burgel Guy, Cohen Jeanine, Coste Michel, Giu R., Maximy René de, Parent Michel, Querrien Anne, Robert M., Robin Christelle, Vieillard -Baron H. L'éthique, exigence professionnelle ou impératif social ; acteurs et chercheurs, deux mondes, deux morales ? Transparence et réserve ; éthique et esthétique. In: Villes en parallèle, n°17-18, avril 1991. Acteurs et chercheurs dans la ville. pp. 255-263

Towards a History of Mass Violence in the Etat Indépendant du Congo, 1885-1908

The present article provides an up-to-date scholarly introduction to mass violence in the Etat Indépendant du Congo (Congo Free State, EIC). Its aims are twofold: to offer a point of access to the extensive literature and historical debates on the subject, and to make the case for exchanging the currently prevalent top-down narrative, with its excessive focus on King Leopold's character and motives, for one which considers the EIC's culture of violence as a multicausal, broadly based and deeply engrained social phenomenon. The argument is divided into five sections. Following a general outline of the EIC's violent system of administration, I discuss its social and demographic impact (and the controversy which surrounds it) to bring out the need for more regionally focused and context sensitive studies. The dispute surrounding demographics demonstrates that what is fundamentally at stake is the place the EIC's extreme violence should occupy in the history of European ‘modernity’. Since approaches which hinge on Leopoldian exceptionalism are particularly unhelpful in clarifying this issue, I pause to reflect on how such approaches came to dominate the distinct historiographical traditions which emerged in Belgium and abroad before moving on to a more detailed exploration of a selection of causes underlying the EIC's violent nature. While state actors remain in the limelight, I shift the focus from the state as a singular, normative agent, towards the existence of an extremely violent society in which various individuals and social groups within and outside of the state apparatus committed violent acts for multiple reasons. As this argument is pitched at a high level of abstraction, I conclude with a discussion of available source material with which it can be further refined and updated

Sprouty2 Interacts with Protein Kinase Cδ and Disrupts Phosphorylation of Protein Kinase D1*

The Sprouty (Spry) proteins act as inhibitors of the Ras/ERK pathway downstream of receptor tyrosine kinases. In this study, we report a novel interaction between protein kinase C δ (PKCδ) and Spry2. Endogenous PKCδ and Spry2 interact in cells upon basic fibroblast growth factor stimulation, indicating a physiological relevance for the interaction. This interaction appeared to require the full-length Spry2 protein and was conformation-dependent. Conformational constraints were released upon FGFR1 activation, allowing the interaction to occur. Although this interaction did not affect the phosphorylation of PKCδ by another kinase, it reduced the phosphorylation of a PKCδ substrate, protein kinase D1 (PKD1). Spry2 was found to interact more strongly with PKCδ with increasing amounts of PKD1, which indicated that instead of competing with PKD1 for binding with PKCδ, it was more likely to form a trimeric complex with both PKCδ and PKD1. Formation of the complex was found to be dependent on an existing PKCδ-PKD1 interaction. By disrupting the interaction between PKCδ and PKD1, Spry2 was unable to associate with PKCδ to form the trimeric complex. As a consequence of this trimeric complex, the existing interaction between PKCδ and PKD1 was increased, and the transfer of phosphate groups from PKCδ to PKD1 was at least partly blocked by Spry2. The action of Spry2 on PKCδ resulted in the inhibition of both ERK phosphorylation and invasion of PC-3 cells via PKCδ signaling. By disrupting the capacity of PKCδ to phosphorylate its cognate substrates, Spry2 may serve to modulate PKCδ signaling downstream of receptor tyrosine kinases and to regulate the physiological outcome

Direct Association of Sprouty-related Protein with an EVH1 Domain (SPRED) 1 or SPRED2 with DYRK1A Modifies Substrate/Kinase Interactions*

The mammalian SPRED (Sprouty-related protein with an EVH1 domain) proteins include a family of three members, SPRED1–3. Currently, little is known about their biochemistry. The best described, SPRED1, has been shown to inhibit the Ras/ERK pathway downstream of Ras. All three SPREDs have a cysteine-rich domain (CRD) that has high homology to the CRD of the Sprouty family of proteins, several of which are also Ras/ERK inhibitors. In the belief that binding partners would clarify SPRED function, we assayed for their associated proteins. Here, we describe the direct and endogenous interaction of SPRED1 and SPRED2 with the novel kinase, DYRK1A. DYRK1A has become the subject of recent research focus as it plays a central role in Caenorhabditis elegans oocyte maturation and egg activation, and there is strong evidence that it could be involved in Down syndrome in humans. Both SPRED1 and SPRED2 inhibit the ability of DYRK1A to phosphorylate its substrates, Tau and STAT3. This inhibition occurs via an interaction of the CRD of the SPREDs with the kinase domain of DYRK1A. DYRK1A substrates must bind to the kinase to enable phosphorylation, and SPRED proteins compete for the same binding site to modify this process. Our accumulated evidence indicates that the SPRED proteins are likely physiological modifiers of DYRK1A