Attenuation of
            <scp>PKC</scp>
            δ enhances metabolic activity and promotes expansion of blood progenitors

Rao, Tata Nageswara; Gupta, Manoj; Softic, Samir; Wang, Leo D.; Jang, Young C.; Thomou, Thomas; Bézy, Olivier; Kulkarni, Rohit; Kahn, C. Ronald; Wagers, Amy J.

doi:10.15252/embj.2018100409

Cited by 5 publications

(3 citation statements)

References 50 publications

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“…Another study reported that the inhibition of PKCδ promoted metabolic activity and expansion of the hematopoietic stem and progenitor cells partially through the PI3K/Akt pathway. 30 PKCδ-induced alteration of EC function in diabetes was corroborated by a similar Akt inhibition pattern observed in isolated EC from the lungs of diabetic ec-Prkcd f/f mice. The reestablishment of Akt activation in EC of diabetic ec-Prkcd −/− mice confirmed the involvement of PKCδ in diabetes-induced inhibition of the VEGF signaling pathway.…”

Section: Discussionsupporting

confidence: 63%

Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

Croteau

Mercier

Fafard-Couture

et al. 2021

Diabetes and Vascular Disease Research

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Aims: Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. Methods: Nondiabetic and diabetic mice, with ( ec-Prkcd−/−) or without ( ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. Results: Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. Conclusions: Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

show abstract

Section: Discussionsupporting

confidence: 63%

Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

Croteau

Mercier

Fafard-Couture

et al. 2021

Diabetes and Vascular Disease Research

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“…Polarized secretion guarantees the antigen specificity of the final response in many cell lineages of the immune system, including innate NK cells [66,67], CTL [5,38], B lymphocytes [29,62], primary CD4 + T cells [68] and Jurkat cells [38]. The association of the absence of PKCδ with the generation of B and T lymphoproliferative disorders both in human and mice [69,70], and the participation of PKCδ in the homoeostasis of blood progenitors [71], support the important role of PKCδ in maintaining cell homoeostasis. Further approaches are needed to extend our results regarding the contribution of PKCδ-dependent centrosomal area F-actin to polarized and focused secretion in directional and invasive cell migration, both of lymphoid and non-lymphoid cells.…”

Section: Discussionmentioning

confidence: 99%

Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

Bello-Gamboa

Velasco

Moreno

et al. 2020

J of Extracellular Vesicle

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T-cell receptor stimulation induces the convergence of multivesicular bodies towards the microtubuleorganizing centre (MTOC) and the polarization of the MTOC to the immune synapse (IS). These events lead to exosome secretion at the IS. We describe here that upon IS formation centrosomal area F-actin decreased concomitantly with MTOC polarization to the IS. PKCδ-interfered T cell clones showed a sustained level of centrosomal area F-actin associated with defective MTOC polarization. We analysed the contribution of two actin cytoskeleton-regulatory proteins, FMNL1 and paxillin, to the regulation of cortical and centrosomal F-actin networks. FMNL1β phosphorylation and F-actin reorganization at the IS were inhibited in PKCδ-interfered clones. F-actin depletion at the central region of the IS, a requirement for MTOC polarization, was associated with FMNL1β phosphorylation at its C-terminal, autoregulatory region. Interfering all FMNL1 isoforms prevented MTOC polarization; nonetheless, FMNL1β re-expression restored MTOC polarization in a centrosomal area F-actin reorganization-independent manner. Moreover, PKCδ-interfered clones exhibited decreased paxillin phosphorylation at the MTOC, which suggests an alternative actin cytoskeleton regulatory pathway. Our results infer that PKCδ regulates MTOC polarization and secretory traffic leading to exosome secretion in a coordinated manner by means of two distinct pathways, one involving FMNL1β regulation and controlling F-actin reorganization at the IS, and the other, comprising paxillin phosphorylation potentially controlling centrosomal area F-actin reorganization.

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“…Polarized secretion guarantees the antigen specificity of the final response in many cell lineages of the immune system, including innate NK cells[66,67], CTL[5,38], B lymphocytes[29] [62], primary CD4+ T cells[68] and Jurkat cells[38]. The association of the absence of PKCδ with the generation of B and T lymphoproliferative disorders both in human and mice[69] [70], and the participation of PKCδ in the homeostasis of blood progenitors[71],support the important role of PKCδ in maintaining cell homeostasis. Further approaches are needed to extend our results regarding the contribution of PKCδdependent centrosomal area F-actin to polarized and focused secretion in directional and invasive cell migration, both of lymphoid and non-lymphoid cells.…”

mentioning

confidence: 99%

Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

Bello-Gamboa

Velasco

Moreno

et al. 2020

Preprint

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T-cell receptor stimulation induces the convergence of multivesicular bodies towards the microtubule-organizing center (MTOC) and the polarization of the MTOC to the immune synapse (IS). These events lead to exosome secretion at the IS. We describe here that upon IS formation centrosomal area F-actin decreased concomitantly with MTOC polarization to the IS. PKCδ-interfered T cell clones showed a sustained level of centrosomal area F-actin associated with defective MTOC polarization. We analysed the contribution of two actin cytoskeleton-regulatory proteins, FMNL1 and paxillin, to the regulation of cortical and centrosomal F-actin networks. FMNL1β phosphorylation and F-actin reorganization at the IS were inhibited in PKCδ-interfered clones. F-actin depletion at the central region of the IS, a requirement for MTOC polarization, was associated with FMNL1β phosphorylation at its C-terminal, autoregulatory region. Interfering all FMNL1 isoforms prevented MTOC polarization; nonetheless, FMNL1β re-expression restored MTOC polarization in a centrosomal area F-actin reorganization-independent manner. Moreover, PKCδ-interfered clones exhibited decreased paxillin phosphorylation at the MTOC, which suggests an alternative actin cytoskeleton regulatory pathway. Our results infer that PKCδ regulates MTOC polarization and secretory traffic leading to exosome secretion in a coordinated manner by means of two distinct pathways, one involving FMNL1β regulation and controlling F-actin reorganization at the IS, and the other, comprising paxillin phosphorylation potentially controlling centrosomal area F-actin reorganization. 3 Keywords: T lymphocytes / immune synapse / actin cytoskeleton/ protein kinase C δ / centrosome / multivesicular bodies / FMNL1 / paxillin / Abbreviations: Ab, antibody; AICD, activation-induced cell death; AIP, average intensity projection; APC, antigen-presenting cell; BCR, B-cell receptor for antigen; C , center of mass; cent2, centrin 2; cIS, central region of the immune synapse; CMAC, CellTracker™ Blue (7-amino-4-chloromethylcoumarin); cSMAC, central supramolecular activation cluster; CTL, cytotoxic T lymphocytes; DAG, diacylglycerol; DGKα, diacylglycerol kinase α; Dia1, Diaphanous-1; dSMAC, distal supramolecular activation cluster; ECL, enhanced chemiluminescence; ESCRT, endosomal sorting complex required for traffic; F-actin, filamentous actin; Fact-low cIS, F-actin-low region at the centre of the immune synapse; FasL, Fas ligand; FMNL1, formin-like 1; fps, frames per second; GFP, green fluorescent protein; HBSS, Hank's balanced salt solution; HRP, horseradish peroxidase; ILV, intraluminal vesicles; IS, immune synapse; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; MIP, maximal intensity projection; MVB, multivesicular bodies; MTOC, microtubuleorganizing center; NS, not significant; PBL, peripheral blood lymphocytes; PKC, protein kinase C; PKCδ, protein kinase C δ isoform; PLC, phospholipase C; PMA, phorbol myristate acetate; Pol. Index, polarization index; pSMAC, peripheral sup...

show abstract

Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors

Cited by 5 publications

References 50 publications

Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

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