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• W2967845993 abstract "In this issue of Acta Physiologica, Benz et al study the role of one important protein in the cyclic AMP signalling pathway, the A-kinase anchoring (AKAP)12.1 The downstream effects stemming from cAMP release are tightly controlled and activate a profusion of signalling pathways. However, many of these different processes function with largely the same major constituent proteins, including adenylate cyclases, kinases, phosphatases and phosphodiesterases. cAMP-dependent protein kinase (PKA), which is the main intracellular target for cAMP, is widely found in these signalling assemblies, and is present at high concentrations in many tissues, playing varied roles in the regulation of molecular processes. Unexpectedly, despite its ubiquity there are only four isoforms of PKA regulatory subunit with which to impart functional and locational specificity. However, we have increasingly come to understand that signalling interactions are governed not only by the global abundance of proteins in a cell, but also from their interactions with each other in organized subcellular microdomains, which mediate spatial and temporal precision into signalling events. These microdomains are largely coordinated by scaffolding proteins, which regulate processes by binding to and localizing the interacting proteins in fixed relationships to one another and to the subcellular architecture. Through these interactions scaffolding proteins dictate where, when and how molecular signalling events progress. Control of PKA localization is defined not only by differences in its own isoforms, but also by its association with a diverse class of scaffolding proteins containing around 50 members, known as AKAPs.2 Although the presence of a PKA binding site designates these proteins as AKAPs, the name belies the important role they often play in binding additional proteins and synchronizing large multi-member complexes, which serve to integrate signals from diverse pathways. AKAP12, alternatively known as gravin or SSeCKS, binds selectively to one of the two types of PKA regulatory subunits, that is, the type II regulatory subunit, as well as to other proteins including protein kinase C (PKC), calmodulin, Src and to cytoskeletal elements (Nauert et al, 1997, Reviewed in Gelman 2010).3, 4 The diversity of reported binding partners of AKAP12 is illustrative of the ability of these scaffolding proteins to act as signalling hubs for disparate signalling systems. In this issue of Acta Physiologica, Benz and colleagues present their findings on the role AKAP12 plays in endothelial cell migration and angiogenesis.1 Through a combination of biochemical, proteomic and imaging techniques, the authors detail how AKAP12 expression in migrating endothelial cells may coordinate the integration of angiogenic stimuli and PKA activity-induced changes in actin dynamics that drive cell movement. In this work, Benz and co-workers addressed both the differential expression of AKAP12 in migrating cells, and its functional role in coordinating signal integration that helps to drive endothelial cell motility. The authors made use of fluorescence-based cell imaging techniques that showed AKAP12 expression is greater in actively migrating cells than quiescent cells, and that much of this AKAP12 is localized in the lamellipodia. They also noted that this limited expression may have led to the initial mischaracterization of AKAP12 as absent from endothelial cells. They further showed that AKAP12 is colocalized with actin-related protein 3 (Arp3) and vasodilator-stimulated phosphoprotein (VASP), both of which play a role in actin elongation, and that this localization takes place largely at the leading edge of the cell.5-7 The upregulation of AKAP12, which is induced by conditions that initiate cell migration, helps to demonstrate that differential expression of scaffolding proteins may be used by the cell to tune the interactions of existing proteins in response to changing cellular needs. Benz and colleagues further showed, through the use of a modified spheroid assay, that siRNA knockdown of AKAP12 in primary cultures of human cells resulted in significantly decreased sprouting following VEGF treatment as compared to controls. This finding was recapitulated in an aortic ring sprouting assay using AKAP12 knockout mice, as well in a wound healing assay using primary cells cultured from the same mouse line. The authors also used retinal angiogenesis as a method to assess the importance of the AKAP12 knockout. The AKAP12−/− retinas showed decreased mitosis as well as a decreased rate of migration when compared to wild type, though the density of the vasculature as characterized by visualization with the endothelial marker isolectin B4 indicated that the knockout animals did not show a markedly decreased presence of endothelial cells. These experiments together also serve to highlight the importance of spatiotemporal control in these signalling processes. In both the siRNA knockdown and the knockout animal model, the removal of the scaffolding protein seems to have precluded the interactions underlying cell motility. These results highlight the importance of microdomains in cellular function. This is especially evident in the modified spheroid assays, in which the results of the knockdown of AKAP12 are largely reiterated by the knockdowns of ARP3 and VASP, showing that the disruption of the spatiotemporal organization of the proteins produces much the same effects as their complete removal from the system. In an effort to identify the molecular mechanisms underlying these results, the authors showed that the phosphorylation of VASP at serine 157, which is a PKA substrate, could be largely disrupted by siRNA knockdown of AKAP12 in endothelial cells. Previous studies have shown the phosphorylation of VASP at serine 157 to drive localization to the leading edge of migrating cells.8, 9 Similar reductions in VASP phosphorylation at serine 157 were achieved using the PKA anchoring disruptor peptide HT31, and by the PKA inhibitor molecule H89. These results help to indicate that disrupting the localization of PKA may play a similar role to inhibiting the kinase in the context of VASP phosphorylation, supporting the importance of spatial proximity imparted to the substrate and kinase by AKAP12 interaction. There remains a great deal to be elucidated surrounding VEGF receptor signal transduction in the context of cell motility, including in VEGF-induced remodelling of the actin cytoskeleton. However, the work of Benz and colleagues shows the importance of AKAP12 in the transduction of the signal from the VEGF receptor, and strongly indicates the presence of a coordinated VASP-AKAP12-PKA complex, which may in turn help to direct future research on the systems governing this cellular response. This work also illustrates how our understanding of the role of subcellular microdomains in signalling pathways is unfolding, and how scaffolds govern the localization and interaction of constituents to generate specificity in systems that otherwise consist of the same pieces. The authors declare that they do not have a conflict of interest." @default.
• W2967845993 created "2019-08-22" @default.
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• W2967845993 date "2019-09-02" @default.
• W2967845993 modified "2023-09-28" @default.
• W2967845993 title "The role of AKAP12 in coordination of VEGF‐induced endothelial cell motility" @default.
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• W2967845993 doi "https://doi.org/10.1111/apha.13359" @default.
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