Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Pike, Kelly A.; Kulkarni, Surendra U.; Pawson, Tony

doi:10.1073/pnas.1018224108

Cited by 24 publications

(28 citation statements)

References 31 publications

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“…Indeed, several studies linked Scrib to migratory processes in epithelial cells, fibroblasts, and lymphocytes. 20 There is, however, little consensus on the specific role and functions of Scrib during migration, and its localization reportedly varies between cells and assay systems used. In epithelial Madin Darby canine kidney (MDCK) cells, Scrib downregulation induces cell migration in Boyden chamber experiments, 16 whereas in breast carcinoma cells (T47D, MCF10A) and fibroblasts Scrib downregulation reduced cell migration.…”

Section: Discussionmentioning

confidence: 99%

The Polarity Protein Scrib Is Essential for Directed Endothelial Cell Migration

Michaelis

Chavakis

Kruse

et al. 2013

Circulation Research

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Rationale: Polarity proteins are involved in the apico-basal orientation of epithelial cells, but relatively little is known regarding their function in mesenchymal cells. Objective: We hypothesized that polarity proteins also contribute to endothelial processes like angiogenesis. Methods and Results: Screening of endothelial cells revealed high expression of the polarity protein Scribble (Scrib). On fibronectin-coated carriers Scrib siRNA (siScrib) blocked directed but not random migration of human umbilical vein endothelial cells and led to an increased number and disturbed orientation of cellular lamellipodia. Coimmunoprecipitation/mass spectrometry and glutathione S-transferase (GST) pulldown assays identified integrin α5 as a novel Scrib interacting protein. By total internal reflection fluorescence (TIRF) microscopy, Scrib and integrin α5 colocalize at the basal plasma membrane of endothelial cells. Western blot and fluorescence activated cell sorting (FACS) analysis revealed that silencing of Scrib reduced the protein amount and surface expression of integrin α5 whereas surface expression of integrin αV was unaffected. Moreover, in contrast to fibronectin, the ligand of integrin α5, directional migration on collagen mediated by collagen-binding integrins was unaffected by siScrib. Mechanistically, Scrib supported integrin α5 recycling and protein stability by blocking its interaction with Rab7a, its translocation into lysosomes, and its subsequent degradation by pepstatin-sensitive proteases. In siScrib-treated cells, reinduction of the wild-type protein but not of PSD95, Dlg, ZO-1 (PDZ), or leucine rich repeat domain mutants restored integrin α5 abundance and directional cell migration. The downregulation of Scrib function in Tg(kdrl:EGFP) s843 transgenic zebrafish embryos delayed the angiogenesis of intersegmental vessels. Conclusions: Scrib is a novel regulator of integrin α5 turnover and sorting, which is required for oriented cell migration and sprouting angiogenesis.

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Section: Discussionmentioning

confidence: 99%

The Polarity Protein Scrib Is Essential for Directed Endothelial Cell Migration

Michaelis

Chavakis

Kruse

et al. 2013

Circulation Research

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“…As others before, we observed that T cell aggregation depended on ERK1/2 signaling (22,49), as the addition of an inhibitor of ERK1/2 signaling abrogated the formation of large aggregates. T cell aggregation has been described to correlate with T cell migration (43,44). Other viruses, like human T cell lymphotropic virus type 1 (HTLV-1) and the betaherpesvirus human cytomegalovirus (HCMV), trigger migration of virus-inoculated leukocytes (50,51).…”

Section: Discussionmentioning

confidence: 99%

“…T cell aggregation is often associated with increased cellular motility (43,44). We therefore assessed whether PRV gE triggers T cell migration.…”

Section: Addition Of Recombinant Ge To Jurkat T Cells Leads To Rapidmentioning

confidence: 99%

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

Pontes

Devriendt

Favoreel

2015

J Virol

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The interaction between viruses and immune cells of the host may lead to modulation of intracellular signaling pathways and to subsequent changes in cellular behavior that are of benefit for either virus or host. ERK1/2 (extracellular signal regulated kinase 1/2) signaling represents one of the key cellular signaling axes. Here, using wild-type and gE null virus, recombinant gE, and gEtransfected cells, we show that the gE glycoprotein of the porcine Varicellovirus pseudorabies virus (PRV) triggers ERK1/2 phosphorylation in Jurkat T cells and primary porcine T lymphocytes. PRV-induced ERK1/2 signaling resulted in homotypic T cell aggregation and increased motility of T lymphocytes. Our study reveals a new function of the gE glycoprotein of PRV and suggests that PRV, through activation of ERK1/2 signaling, has a substantial impact on T cell behavior. IMPORTANCEHerpesviruses are known to be highly successful in evading the immune system of their hosts, subverting signaling pathways of the host to their own advantage. The ERK1/2 signaling pathway, being involved in many cellular processes, represents a particularly attractive target for viral manipulation. Glycoprotein E (gE) is an important virulence factor of alphaherpesviruses, involved in viral spread. In this study, we show that gE has the previously uncharacterized ability to trigger ERK1/2 phosphorylation in T lymphocytes. We also show that virus-induced ERK1/2 signaling leads to increased migratory behavior of T cells and that migratory T cells can spread the infection to susceptible cells. In conclusion, our results point to a novel function for gE and suggest that virus-induced ERK1/2 activation may trigger PRV-carrying T lymphocytes to migrate and infect other cells susceptible to PRV replication.A lphaherpesviruses constitute the largest subfamily of the herpesviruses. This subfamily contains closely related pathogens, including herpes simplex virus 1 (HSV-1), HSV-2, and varicellazoster virus (VZV) in humans. Another member of the alphaherpesvirus subfamily is the porcine pseudorabies virus (PRV), which is often used as a model to study general features of alphaherpesvirus biology (1).PRV encodes 11 glycoproteins (2) incorporated in the viral envelope, which are embedded in different host membranes of the infected cell, including the plasma membrane. One of these glycoproteins is glycoprotein E (gE), which is important for virulence and viral (neuronal) spread (3-10). For both PRV and HSV-1, there are indications that gE may have a signaling function in immune cells, as it drives signaling-dependent processes like cell surface antigen capping (11-13). However, to date, there are no reports that gE indeed triggers any particular signaling pathway.The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway, controlling many fundamental cellular events, such as cell proliferation, survival, differentiation, migration, apoptosis, and metabolism (14-16). It ma...

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“…Scribble inhibition in fetal liver progenitor cells results in a partial block during DN3 progression. 37 Down-regulation of Ptcra and Scrib correlates with the delayed DN23DN3 progression and could contribute to the increased proportion of ETP/DN2 thymocytes observed in the presence of Wnt4 in vivo and in vitro. In various cell types, Wnt4 can elicit canonical, noncanonical, or both types of Wnt signaling.…”

Section: Wnt4 In Fetal and Postnatal Thymopoiesis 5167mentioning

confidence: 99%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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Immature T-cell clustering and efficient differentiation require the polarity protein Scribble

Cited by 24 publications

References 31 publications

The Polarity Protein Scrib Is Essential for Directed Endothelial Cell Migration

The Polarity Protein Scrib Is Essential for Directed Endothelial Cell Migration

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

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