Control of atypical PKCι membrane dissociation by tyrosine phosphorylation within a PB1-C1 interdomain interface

Atypical PKCs are cell polarity kinases that operate at the plasma membrane where they function within multiple molecular complexes to contribute to the establishment and maintenance of polarity. In contrast to the classical and novel PKCs, atypical PKCs do not respond to diacylglycerol cues to bind the membrane compartment. Until recently it was not clear how aPKCs are recruited; whether aPKCs can directly interact with membranes or whether they are dependent on other protein interactors to do so. Two recent studies identified the pseudo-substrate region and the C1 domain as direct membrane interaction modules, however their relative importance and coupling are unknown. We combined molecular modelling and functional assays to show that the regulatory module of aPKCι, comprising the PB1 pseudo-substrate and C1 domains, forms a cooperative and spatially continuous invariant membrane interaction platform. Furthermore, we show the coordinated orientation of membrane-binding elements within the regulatory module requires a key PB1-C1 interfacial β-strand (BSL). We show this element contains a highly conserved Tyr residue that can be phosphorylated and that negatively regulates the integrity of the regulatory module, leading to membrane release. We thus expose a novel regulatory mechanism of aPKCι membrane binding and release during cell polarization

Into the fold: advances in understanding aPKC membrane dynamics

Atypical protein kinase Cs (aPKCs) are part of the PKC family of protein kinases and are atypical because they don’t respond to the canonical PKC activators diacylglycerol (DAG) and Ca2+. They are central to the organization of polarized cells and are deregulated in several cancers. aPKC recruitment to the plasma membrane compartment is crucial to their encounter with substrates associated with polarizing functions. However, in contrast with other PKCs, the mechanism by which atypical PKCs are recruited there has remained elusive until recently. Here, we bring aPKC into the fold, summarizing recent reports on the direct recruitment of aPKC to membranes, providing insight into seemingly discrepant findings and integrating them with existing literature

The Rho family GEF FARP2 is activated by aPKC iota to control tight junction formation and polarity

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Among the controls determining polarity are the PAR proteins, PAR6, aPKCι and PAR3, regulating both known and unknown effectors. Here, we identify FARP2 as a ‘RIPR’ motif-dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain–kinase domain interaction and detachment promoted by aPKCι-dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42, which is consistent with it being involved in upstream regulation of the polarising PAR6–aPKCι complex. However, we show that aPKCι acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCι−FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCι and other Cdc42 effectors

Handicap et citoyenneté une approche interdisciplinaire

De manière générale, le concept de citoyenneté a considérablement évolué. En ce qui concerne le handicap, le passage d’un modèle médical à un modèle social et ensuite à un point de vue psychosocial et pluridisciplinaire a transformé les modalités d’intervention. Les personnes en situation de handicap de bénéficiaires-usagers sont devenues des bénéficiaires-experts, socialement incluses plutôt qu’insérées. Une justice sociale réellement inclusive ne peut s’instaurer qu’à travers des processus d’apprentissages de l’ensemble des personnes concernées, usagers, professionnels, chercheurs, experts, politiques

L'exercice des droits et l'émancipation sexuelle des personnes ayant une déficience intellectuelle: Une éthique de la citoyenneté

Improving the sexual lives of people with disabilities (PWDs) and people with an intellectual disability (ID) requires not only changes in the service organizations and professional practices, but it is primarily based on an ongoing dialogue between stakeholders, including first and foremost, people with ID. Under the "International Education Program for Democratic Citizenship" by, for and with individuals with a mental, intellectual or physical disability, the issue of sexual rights has emerged as one of the major challenges empowering people with ID. Although several stakeholders have contributed to the emergence of a new emancipatory paradigm, based on the recognition and exercise of rights of people with disabilities, it is essential that PWDs and people with ID be heard and participate in the cultural, ethical, political, organizational or professional ongoing changes because the recognition of sexual rights is part of the political universe of citizenship and civic engagement. From words to political action through social changes, people with intellectual disabilities still have a long way to go and society has to consider major changes, so they can individually and collectively exercise all their rights

Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d] pyrimidine analogues

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.crosscheck: This document is CrossCheck deposited related_data: Supplementary Information identifier: Klaas Verschueren (ORCID) identifier: Joachim Demaerel (ORCID) identifier: Arnout R. D. Voet (ResearcherID) identifier: Wim M. De Borggraeve (ORCID) identifier: Wim M. De Borggraeve (ResearcherID) copyright_licence: The Royal Society of Chemistry has an exclusive publication licence for this journal copyright_licence: This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) history: Received 2 December 2016; Accepted 31 January 2017; Accepted Manuscript published 9 February 2017; Advance Article published 15 February 2017; Version of Record published 23 March 2017status: publishe

Equivocal, explicit and emergent actions of PKC isoforms in cancer

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions, and evolving insights into tumour- associated functions, reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this eco-system, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but the when and how is not obvious