Journal articles: 'Scribble protein'

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Liu, Hongbing, Lisa Golebiewski, Eugene C. Dow, Robert M. Krug, Ronald T. Javier, and Andrew P. Rice. "The ESEV PDZ-Binding Motif of the Avian Influenza A Virus NS1 Protein Protects Infected Cells from Apoptosis by Directly Targeting Scribble." Journal of Virology 84, no. 21 (August 11, 2010): 11164–74. http://dx.doi.org/10.1128/jvi.01278-10.

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ABSTRACT The NS1 protein from influenza A viruses contains a four-amino-acid sequence at its carboxyl terminus that is termed the PDZ-binding motif (PBM). The NS1 PBM is predicted to bind to cellular PDZ proteins and functions as a virulence determinant in infected mice. ESEV is the consensus PBM sequence of avian influenza viruses, while RSKV is the consensus sequence of human viruses. Currently circulating highly pathogenic H5N1 influenza viruses encode an NS1 protein with the ESEV PBM. We identified cellular targets of the avian ESEV PBM and identified molecular mechanisms involved in its function. Using glutathione S-transferase (GST) pull-down assays, we found that the ESEV PBM enables NS1 to associate with the PDZ proteins Scribble, Dlg1, MAGI-1, MAGI-2, and MAGI-3. Because Scribble possesses a proapoptotic activity, we investigated the interaction between NS1 and Scribble. The association between NS1 and Scribble is direct and requires the ESEV PBM and two Scribble PDZ domains. We constructed recombinant H3N2 viruses that encode an H6N6 avian virus NS1 protein with either an ESEV or mutant ESEA PBM, allowing an analysis of the ESEV PBM in infections in mammalian cells. The ESEV PBM enhanced viral replication up to 4-fold. In infected cells, NS1 with the ESEV PBM relocalized Scribble into cytoplasmic puncta concentrated in perinuclear regions and also protected cells from apoptosis. In addition, the latter effect was eliminated by small interfering RNA (siRNA)-mediated Scribble depletion. This study shows that one function of the avian ESEV PBM is to reduce apoptosis during infection through disruption of Scribble's proapoptotic function.

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Bonello, Teresa T., and Mark Peifer. "Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation." Journal of Cell Biology 218, no. 3 (December 31, 2018): 742–56. http://dx.doi.org/10.1083/jcb.201810103.

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Key events ranging from cell polarity to proliferation regulation to neuronal signaling rely on the assembly of multiprotein adhesion or signaling complexes at particular subcellular sites. Multidomain scaffolding proteins nucleate assembly and direct localization of these complexes, and the protein Scribble and its relatives in the LAP protein family provide a paradigm for this. Scribble was originally identified because of its role in apical–basal polarity and epithelial integrity in Drosophila melanogaster. It is now clear that Scribble acts to assemble and position diverse multiprotein complexes in processes ranging from planar polarity to adhesion to oriented cell division to synaptogenesis. Here, we explore what we have learned about the mechanisms of action of Scribble in the context of its multiple known interacting partners and discuss how this knowledge opens new questions about the full range of Scribble protein partners and their structural and signaling roles.

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Javorsky, Airah, Patrick O. Humbert, and Marc Kvansakul. "Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble." Viruses 14, no. 3 (March 11, 2022): 583. http://dx.doi.org/10.3390/v14030583.

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Scribble is a highly conserved regulator of cell polarity, a process that enables the generation of asymmetry at the cellular and tissue level in higher organisms. Scribble acts in concert with Disc-large (Dlg) and Lethal-2-giant larvae (Lgl) to form the Scribble polarity complex, and its functional dysregulation is associated with poor prognosis during viral infections. Viruses have been shown to interfere with Scribble by targeting Scribble PDZ domains to subvert the network of interactions that enable normal control of cell polarity via Scribble, as well as the localisation of the Scribble module within the cell. The influenza A virus NS1 protein was shown to bind to human Scribble (SCRIB) via its C-terminal PDZ binding motif (PBM). It was reported that the PBM sequence ESEV is a virulence determinant for influenza A virus H5N1 whilst other sequences, such as ESKV, KSEV and RSKV, demonstrated no affinity towards Scribble. We now show, using isothermal titration calorimetry (ITC), that ESKV and KSEV bind to SCRIB PDZ domains and that ESEV unexpectedly displayed an affinity towards all four PDZs and not just a selected few. We then define the structural basis for the interactions of SCRIB PDZ1 domain with ESEV and ESKV PBM motifs, as well as SCRIB PDZ3 with the ESKV PBM motif. These findings will serve as a platform for understanding the role of Scribble PDZ domains and their interactions with different NS1 PBMs and the mechanisms that mediate cell polarity within the context of the pathogenesis of influenza A virus.

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Hegde, Shailaja N., Mark J. Althoff, Ramesh C. Nayak, Ashley M. Wellendorf, Fatima Mohmoud, Gang Huang, Yi Zheng, Maria T. Diaz-Meco, Jorge Moscat, and Jose A. Cancelas. "Basal Polarity Complex Scribble Is Required for Leukemic Initiation and Propagation through Negative Regulation of Apical Polarity Complex Activator Cdc42 and Hypoxia Inducing Factor-1α." Blood 132, Supplement 1 (November 29, 2018): 551. http://dx.doi.org/10.1182/blood-2018-99-118919.

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Abstract Despite the introduction of tyrosine kinase inhibitor and CAR-T cell therapies, the prognosis for Ph+ and Ph-like acute lymphoblastic leukemia remains poor. In the present study, we show the role of the Scribble protein in both lymphoid and myeloid leukemogenesis. The polarity protein Scribble is a member of the basal polarity complex, which is down-regulated in many cancers, suggesting a possible tumor suppressor role, especially in so-called cancer initiating cells. Its effect and mechanisms of activity in leukemic cell fate along with its potential activity on leukemic initiating cells have only been recently started to elucidated. Using interferon-responsive inducible (Mx1-Cre) Scribble-deficient mice, we have characterized the role of Scribble in both retroviral transduction, transplantation animal models and binary, inducible stem cell initiated (Scl-tTA/TRE-BCR-ABL) serial propagation models of BCR-ABL induced leukemia. We found that Scribble expression is upregulated at both transcriptional and translational levels in p210- or p190-BCR-ABL induced leukemic progenitors. In vitro, leukemic colony formation was impaired in Scribble deficient leukemic progenitors (~48% reduction; p≤ 0.05, compared to Wt leukemic progenitors) demonstrating that Scribble is important for leukemogenesis. In vivo, the deletion of Scribble abrogates the development of myeloproliferative disease induced by p210-BCR-ABL (median survival: 70 vs 47 days in Scribble deficient and Wt chimeric mice, respectively; p≤0.05); and significantly impairs B-cell lymphoid leukemogenesis induced by p190-BCR-ABL (median survival: 80 vs 60 days for Scribble deficient and Wt chimeric animals, respectively). Mechanistically, BCR-ABL activates the apical polarity regulator Cdc42 in leukemic progenitors and this activation is inhibited by the deficiency of Scribble. The deficiency of Cdc42 does not impair leukemogenesis but the combined deficiency of Cdc42 and Scribble restores the in vivo survival (median survival: 47 days, p≤0.01 compared to Scribble deficient mice) in chimeric p190-BCR-ABL+ leukemic mice to levels similar to wild-type leukemic cells. These data indicate that Scribble-deficient leukemogenesis is dependent on oncogene induced Cdc42 activity in lymphoid progenitors. Furthermore, Scribble deficiency in leukemic progenitors increases the activation of the AMPK/mTORC1 signaling pathway and the protein expression and transcriptional activity of its downstream effector hypoxia-inducing factor-1α (HIF-1α). HIF-1α silencing by constitutive shRNA expression or inducible deletion in Scribble deleted B-lymphoid leukemic cells restored leukemic progenitor clonogenic efficiency (CFU average: 52 vs 110 per 1,000 B220+/EGFP+ BM cells, in Scribble and double Scribble/HIF-1α deficient, respectively; p≤0.01) and B-lymphoid leukemogenesis in vivo (median survival of 62 days; p≤0.05 compared with Scribble deficient chimeric animals). In addition, double deficiency of Scribble and HIF-1α restored AMPK/mTORC1 signaling to Wt leukemic levels. This data indicates that Scribble is a negative regulator of HIF-1α expression and activity, and the restoration of HIF-1α expression and activity to normal leukemic levels is necessary to restore leukemogenesis. Altogether, our data indicates that Scribble is a positive regulator of oncogenesis in leukemic progenitors, in vitro and in vivo, through Cdc42 and HIF-1α activities. Disclosures No relevant conflicts of interest to declare.

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Pieczynski, Jay, and Ben Margolis. "Protein complexes that control renal epithelial polarity." American Journal of Physiology-Renal Physiology 300, no. 3 (March 2011): F589—F601. http://dx.doi.org/10.1152/ajprenal.00615.2010.

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Establishment of epithelial apicobasal polarity is crucial for proper kidney development and function. In recent years, there have been important advances in our understanding of the factors that mediate the initiation of apicobasal polarization. Key among these are the polarity complexes that are evolutionarily conserved from simple organisms to humans. Three of these complexes are discussed in this review: the Crumbs complex, the Par complex, and the Scribble complex. The apical Crumbs complex consists of three proteins, Crumbs, PALS1, and PATJ, whereas the apical Par complex consists of Par-3, Par-6, and atypical protein kinase C. The lateral Scribble complex consists of Scribble, discs large, and lethal giant larvae. These complexes modulate kinase and small G protein activity such that the apical and basolateral complexes signal antagonistically, leading to the segregation of the apical and basolateral membranes. The polarity complexes also serve as scaffolds to direct and retain proteins at the apical membrane, the basolateral membrane, or the intervening tight junction. There is plasticity in apicobasal polarity, and this is best seen in the processes of epithelial-to-mesenchymal transition and the converse mesenchymal-to-epithelial transition. These transitions are important in kidney disease as well as kidney development, and modulation of the polarity complexes are critical for these transitions.

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Sun, Yu, Mytyl Aiga, Eileen Yoshida, Patrick O. Humbert, and Shernaz X. Bamji. "Scribble Interacts with β-Catenin to Localize Synaptic Vesicles to Synapses." Molecular Biology of the Cell 20, no. 14 (July 15, 2009): 3390–400. http://dx.doi.org/10.1091/mbc.e08-12-1172.

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An understanding of how synaptic vesicles are recruited to and maintained at presynaptic compartments is required to discern the molecular mechanisms underlying presynaptic assembly and plasticity. We have previously demonstrated that cadherin–β-catenin complexes cluster synaptic vesicles at presynaptic sites. Here we show that scribble interacts with the cadherin–β-catenin complex to coordinate vesicle localization. Scribble and β-catenin are colocalized at synapses and can be coimmunoprecipitated from neuronal lysates, indicating an interaction between scribble and β-catenin at the synapse. Using an RNA interference approach, we demonstrate that scribble is important for the clustering of synaptic vesicles at synapses. Indeed, in scribble knockdown cells, there is a diffuse distribution of synaptic vesicles along the axon, and a deficit in vesicle recycling. Despite this, synapse number and the distribution of the presynaptic active zone protein, bassoon, remain unchanged. These effects largely phenocopy those observed after ablation of β-catenin. In addition, we show that loss of β-catenin disrupts scribble localization in primary neurons but that the localization of β-catenin is not dependent on scribble. Our data supports a model by which scribble functions downstream of β-catenin to cluster synaptic vesicles at developing synapses.

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Althoff, Mark J., Ramesh C. Nayak, Shailaja Hegde, Ashley M. Wellendorf, Fatima Mohmoud, Maria T. Diaz-Meco, Jorge Moscat, and Jose A. Cancelas. "Scribble Controls HSC Self-Renewal through Polarity-Dependent Activation of the Hippo Signaling Pathway." Blood 130, Suppl_1 (December 7, 2017): 710. http://dx.doi.org/10.1182/blood.v130.suppl_1.710.710.

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Abstract Search of molecular targets to expand functional hematopoietic stem cells (HSC) for transplantation and hematological cancer therapy remains paramount, particularly when manipulation of cellular quiescence is required. HSC are highly quiescent cells with the ability to rapidly enter the cell cycle in response to microenvironment cues and divide through changes in their polarity. Despite cellular polarity being one of the most basic properties of all living cells, the role that polarity regulators have on polarization and function of HSC remains controversial. Scribble, of the Scribble Polarity Complex, controls the spatial organization of intracellular proteins and negatively regulates the cell cycle. By using a combination of constitutive and inducible hematopoietic-specific Scribble-deficient animal models, hematopoietic reconstitution assays, structure-function mutants of Scribble and intracellular protein trafficking analysis, we identified the functional relevance of Scribble in HSC activity. We observed that Scribble is polarized in HSC and deletion of Scribble leads to a ~ 50% reduction in the bone marrow (BM) HSC population (p<0.001). Scribble-deficient HSC are less quiescent (G0: 93 vs 88%, p<0.05; S/G2/M 4 vs 10%, for WT and KO, respectively, p<0.01) and contain ~70% reduction of dormant, long-term HSC (p<0.01). This data indicates that Scribble is required to maintain HSC quiescence. Functionally, stroma-dependent long-term BM cultures revealed that Scribble-deficient BM contains a ~ 60% reduction in the number of early cobblestone area-forming cells (CAFC) while their content of late (28-35 day) CAFC (primitive progenitors/HSC) is 3-5 fold increased. Serial transplantation experiments demonstrated that Scribble-deficient BM HSC have increased competitive repopulating potential (46% vs 90% BM chimerism for WT and KO BM from tertiary recipient mice, respectively, p<0.001). Moreover, deletion of hematopoietic Scribble protects mice from 5-fluorouracil (5-FU)-mediated hematopoietic exhaustion and death by BM aplasia (>30 days median survival vs 16 days for KO mice, p<0.001). This set of functional data indicates that Scribble deficient HSC show enhanced long-term self-renewal capacity in stroma-dependent cultures and in vivo following transplantation or chemotherapeutic stress without the development of stem cell exhaustion or leukemia. Comparative transcriptional analysis of Scribble-deficient and WT HSC identified transcriptional regulation of the Hippo-dependent signaling pathway. We observed that Yap1 is polarized in a Scribble-dependent manner within WT HSC and co-localizes in the cytoplasm with the active form of the upstream inhibitory kinase, Lats1. Notably, deletion of Scribble in HSC leads to a disruption of the phosphorylated Lats1/Yap1 complex resulting in Yap1 translocation to the nucleus. Subsequently, cytoplasmic polarization of Yap1 can be restored when Scribble-deficient HSC are rescued with full length or PDZ domain containing mutants of Scribble. Expression of the N-terminus leucine-rich repeat (LRR) domain of Scribble successfully restored activation of Lats1 as well as phosphorylated Lats1 co-localization with Scribble, however, was not sufficient to prevent Yap1 translocation. Combined deletion of Yap1 and Taz using an inducible hematopoietic-specific model generates hematopoietic stem and progenitor cells (HSC/P) with enhanced cellular proliferation (HSC G0: 88 vs. 58%, p<0.0001; G1: 6 vs. 25%, p<0.0001; S/G2/M 6 vs. 18%, p<0.0001 for WT controls and Yap1/Taz double deficient BM, respectively) leading to an increase in colony forming units and early CAFC potential (2 and 3 fold respectively; p<0.0001). Yap1/Taz double KO HSC are prone to exhaustion evidenced by their inability to regenerate murine hematopoiesis after serial administration of 5-FU (12 days median survival vs 20 days for WT control mice, p<0.001). Triple deficiency of Scribble, Yap1 and Taz restores the effect of both Scribble and Yap1/Taz deficiencies to a normal hematopoietic response after myeloablation. Altogether, this data identifies Scribble as a negative regulator of cell cycle entry and self-renewal of HSC, and provides compelling evidence of key polarity and signaling programs used to maintain HSC quiescence that can be utilized as novel targets to improve HSC based transplantations and hematological cancer therapies. Disclosures No relevant conflicts of interest to declare.

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Fenner, Annette. "Scribble complex protein deficiency promotes prostate tumors in vivo." Nature Reviews Urology 8, no. 12 (November 15, 2011): 644. http://dx.doi.org/10.1038/nrurol.2011.167.

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Singh, Abhishek K., Mark J. Althoff, Saimul Islam, Ashley M. Wellendorf, and Jose A. Cancelas. "Scribble Is a Negative Regulator of Interferon-I Dependent Notch1 Activation in Adult Hematopoietic Stem Cells and Progenitors." Blood 138, Supplement 1 (November 5, 2021): 299. http://dx.doi.org/10.1182/blood-2021-151046.

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Abstract Hematopoietic stem cells (HSC) are highly quiescent cells with the ability to rapidly enter cell cycle and differentiate through changes in their polarity and the disposition of intracellular molecular fate determinants in response to microenvironment (ME) cues. Interferons type 1 (IFN-I) are ME cytokines produced during the physiological response mounted to combat a viral infection. In bone marrow hematopoiesis, IFN-I induces activation and proliferation of HSC. Clinically, patients treated with IFN-I, as well as individuals suffering from IFN-I associated chronic disease, often exhibit sustained hematological cytopenias and HSC failure. The precise molecular mechanisms that govern HSC behavior in response to IFN-I are still unclear. Our data highlights that Scribble deficient HSC are less sensitive to IFN-I mediated activation. By using hematopoietic specific deletion of Scribble in murine hematopoiesis (Vav-Cre;Scribble KO); we demonstrated that Scribble deficient LSK CD150 +/CD48 - HSC are less responsive to polyinositide-polycytidine (pI:C) induced IFN-I mediated activation and retain cellular quiescence (G0:45±5.4% vs 63±2.7% in WT and Scribble KO, respectively, p<0.05). IFN-I induced upregulation of Sca-1 expression was also significantly hampered in Scribble deficient HSC. Functionally, serial transplantation experiments demonstrated that in response to poly I:C, Scribble deficient HSC display increased competitive repopulating potential (26±1.3% vs 38±1.2% BM chimerism for WT and KO BM in secondary recipients and 38±2.5% vs 48±2.7% BM chimerism in tertiary recipients, p<0.01). The maintenance of cellular quiescence and function for Scribble deficient HSC are independent of canonical IFN-I driven STAT-1 signaling, as we report no differences in STAT-1 activation, nuclear translocation or the expression of STAT-1 canonical target genes in response to pI:C. Unsupervised transcriptomics analysis of Scribble-deficient HSC supported dysregulation of Notch signaling. Furthermore, Scribble deficiency in non-activated LSK HSC and progenitors (HSPC) was associated with constitutive activation and cleavage of Notch1 (Notch1 ICD;~3 fold) at levels comparable to IFN-I mediated activation of WT HSPC. However, Scribble deficient HSPC did not exhibit further Notch1 cleavage activation upon in vivo IFN-I induction. Pharmacological in vivo γ-secretase inhibition (YO-01027) prevented the protective effect of Scribble deficiency on IFN-I dependent loss of HSC quiescence. These data indicate that Notch1 activation, and subsequent cleavage, is indispensable for Scribble deficient HSC quiescence in response to IFN-I. Active Cdc42 is a critical regulator of HSC quiescence and fate, and previous studies have demonstrated that Scribble controls HSC asymmetric division potential and fate through the PDZ mediated scaffolding of cytosolic Yap1 with activated Cdc42 (Cdc42-GTP). Next to determine whether poly I:C mediated Notch1 cleavage linked with Cdc42 activity, we analyzed the protein interactions between cleaved Notch1 and Cdc42-GTP in relation with Scribble. Our findings revealed that Scribble associates with non-cleaved, membrane bound Notch but upon in vivo IFN-I induction Notch1 is cleaved, activated and translocates with Scribble-free, activated Cdc42 to the nucleus of HSC. Deletion of HSC Scribble associated with a reduced (~45%, p<0.001) proximity interaction between cleaved Notch1 and Cdc42-GTP. Collectively our findings identify that Scribble controls IFN-I mediated HSPC activation through induction of Notch1 cleavage and Cdc42 activity, and highlight such interaction as a new potential target to dampen inflammation driven HSC exhaustion. Disclosures Cancelas: Cerus Co: Research Funding; TerumoBCT: Research Funding; Hemanext: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytosorbents Inc: Research Funding; Fresenius-Kabi LLC: Research Funding; Westat Inc: Research Funding; Vascular Solutions Inc.: Research Funding; Hemerus LLC: Research Funding; University of South Florida/MEQU Inc: Research Funding.

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Choi, Jongho, Regina B. Troyanovsky, Indrajyoti Indra, Brian J. Mitchell, and Sergey M. Troyanovsky. "Scribble, Erbin, and Lano redundantly regulate epithelial polarity and apical adhesion complex." Journal of Cell Biology 218, no. 7 (May 30, 2019): 2277–93. http://dx.doi.org/10.1083/jcb.201804201.

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The basolateral protein Scribble (Scrib), a member of the LAP protein family, is essential for epithelial apicobasal polarity (ABP) in Drosophila. However, a conserved function for this protein in mammals is unclear. Here we show that the crucial role for Scrib in ABP has remained obscure due to the compensatory function of two other LAP proteins, Erbin and Lano. A combined Scrib/Erbin/Lano knockout disorganizes the cell–cell junctions and the cytoskeleton. It also results in mislocalization of several apical (Par6, aPKC, and Pals1) and basolateral (Llgl1 and Llgl2) identity proteins. These defects can be rescued by the conserved “LU” region of these LAP proteins. Structure–function analysis of this region determined that the so-called LAPSDb domain is essential for basolateral targeting of these proteins, while the LAPSDa domain is essential for supporting the membrane basolateral identity and binding to Llgl. In contrast to the key role in Drosophila, mislocalization of Llgl proteins does not appear to be critical in the scrib ABP phenotype.

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Clattenburg, Leanne, Michael Wigerius, Jiansong Qi, Jan K. Rainey, Jillian L. Rourke, Shanmugam Muruganandan, Christopher J. Sinal, and James P. Fawcett. "NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling." Molecular and Cellular Biology 35, no. 13 (April 27, 2015): 2265–77. http://dx.doi.org/10.1128/mcb.00062-15.

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Deregulation of cellular polarity proteins and their associated complexes leads to changes in cell migration and proliferation. The nitric oxide synthase 1 adaptor protein (NOS1AP) associates with the tumor suppressor protein Scribble to control cell migration and oncogenic transformation. However, how NOS1AP is linked to the cell signaling events that curb oncogenic progression has remained elusive. Here we identify several novel NOS1AP isoforms, NOS1APd, NOS1APe, and NOS1APf, with distinct cellular localizations. We show that isoforms with a membrane-interacting phosphotyrosine binding (PTB) domain can associate with Scribble and recognize acidic phospholipids. In a screen to identify novel binding proteins, we have discovered a complex consisting of NOS1AP and the transcriptional coactivator YAP linking NOS1AP to the Hippo signaling pathway. Silencing of NOS1AP reduces the phosphorylation of YAP and of the upstream kinase Lats1. Conversely, expression of NOS1AP promotes YAP and Lats1 phosphorylation, which correlates with reduced TEAD activity and restricted cell proliferation. Together, these data implicate a role for NOS1AP in the regulation of core Hippo signaling and are consistent with the idea that NOS1AP functions as a tumor suppressor.

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Ellis, Sarah, Naomi Campanale, Judy Borg, Matthew Reardon, Leah Adolph, Samantha Williams, Patrick Humbert, Carl Walkley, Louise Purton, and Sarah Russell. "Role of the polarity protein, scribble, in hematopoiesis and leukemia." Experimental Hematology 42, no. 8 (August 2014): S31. http://dx.doi.org/10.1016/j.exphem.2014.07.111.

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Pim, David, Vjekoslav Tomaić, and Lawrence Banks. "The Human Papillomavirus (HPV) E6* Proteins from High-Risk, Mucosal HPVs Can Direct Degradation of Cellular Proteins in the Absence of Full-Length E6 Protein." Journal of Virology 83, no. 19 (July 29, 2009): 9863–74. http://dx.doi.org/10.1128/jvi.00539-09.

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ABSTRACT The E6 oncoproteins from high-risk mucosotrophic human papillomaviruses (HPVs) target a range of cellular proteins for proteasome-mediated degradation. Apart from the tumor suppressor p53 and proapoptotic Bcl-2 family member Bak, many targets contain class 1 PDZ domains and are involved in cell junction stability and signaling. The targeting mechanism is considered to function by the E6 protein acting as an adaptor molecule linking a cellular ubiquitin ligase to the target protein. In each case, whether the target is the p53 tumor suppressor or a member of the group of PDZ domain-containing targets, this mechanism relies on a direct interaction between E6 and its cellular target. This study focuses on the impact of the HPV type 18 (HPV-18) E6*I protein on the stability of Akt, Dlg, MAGI-1, MAGI-2, and Scribble. We show that HPV-18 E6* expression can downregulate the expression levels of Akt, Dlg, and Scribble in the absence of full-length HPV-18 E6 protein. The reduction in Dlg levels by E6* is independent of transcription and does not require a direct interaction between the two proteins although the proteasome pathway is involved. Further, we provide evidence that activation of certain signal transduction pathways has a profound effect on the targeting of Dlg by E6* and suggest that high-risk HPV E6 oncoproteins can target certain substrates both directly and indirectly through the E6* proteins and may cooperate in their degradation.

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Bilder, David, and Norbert Perrimon. "Localization of apical epithelial determinants by the basolateral PDZ protein Scribble." Nature 403, no. 6770 (February 2000): 676–80. http://dx.doi.org/10.1038/35001108.

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Hartleben, Björn, Eugen Widmeier, Nicola Wanner, Miriam Schmidts, Sung Tae Kim, Lisa Schneider, Britta Mayer, et al. "Role of the Polarity Protein Scribble for Podocyte Differentiation and Maintenance." PLoS ONE 7, no. 5 (May 7, 2012): e36705. http://dx.doi.org/10.1371/journal.pone.0036705.

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Chen, Haiqi, Dolores D. Mruk, Will M. Lee, and C. Yan Cheng. "Planar Cell Polarity (PCP) Protein Vangl2 Regulates Ectoplasmic Specialization Dynamics via Its Effects on Actin Microfilaments in the Testes of Male Rats." Endocrinology 157, no. 5 (March 18, 2016): 2140–59. http://dx.doi.org/10.1210/en.2015-1987.

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Abstract Planar cell polarity (PCP) proteins confer polarization of a field of cells (eg, elongating/elongated spermatids) within the plane of an epithelium such as the seminiferous epithelium of the tubule during spermatogenesis. In adult rat testes, Sertoli and germ cells were found to express PCP core proteins (eg, Van Gogh-like 2 [Vangl2]), effectors, ligands, and signaling proteins. Vangl2 expressed predominantly by Sertoli cells was localized at the testis-specific, actin-rich ectoplasmic specialization (ES) at the Sertoli-spermatid interface in the adluminal compartment and also Sertoli-Sertoli interface at the blood-testis barrier (BTB) and structurally interacted with actin, N-cadherin, and another PCP/polarity protein Scribble. Vangl2 knockdown (KD) by RNA interference in Sertoli cells cultured in vitro with an established tight junction-permeability barrier led to BTB tightening, whereas its overexpression using a full-length cDNA construct perturbed the barrier function. These changes were mediated through an alteration on the organization actin microfilaments at the ES in Sertoli cells, involving actin-regulatory proteins, epidermal growth factor receptor pathway substrate 8, actin-related protein 3, and Scribble, which in turn affected the function of adhesion protein complexes at the ES during the epithelial cycle of spermatogenesis. Using Polyplus in vivo-jetPEI reagent as a transfection medium to silence Vangl2 in the testis in vivo by RNA interference with high efficacy, Vangl2 KD led to changes in F-actin organization at the ES in the epithelium, impeding spermatid and phagosome transport and spermatid polarity, meiosis, and BTB dynamics. For instance, step 19 spermatids remained embedded in the epithelium alongside with step 9 and 10 spermatids in stages IX-X tubules. In summary, the PCP protein Vangl2 is an ES regulator through its effects on actin microfilaments in the testis.

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Phua, Dominic C. Y., Patrick O. Humbert, and Walter Hunziker. "Vimentin Regulates Scribble Activity by Protecting It from Proteasomal Degradation." Molecular Biology of the Cell 20, no. 12 (June 15, 2009): 2841–55. http://dx.doi.org/10.1091/mbc.e08-02-0199.

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Scribble (Scrib), Discs large, and Lethal giant larvae form a protein complex that regulates different aspects of cell polarization, including apical–basal asymmetry in epithelial cells and anterior–posterior polarity in migrating cells. Here, we show that Scrib interacts with the intermediate filament cytoskeleton in epithelial Madin-Darby canine kidney (MDCK) cells and endothelial human umbilical vein endothelial cells. Scrib binds vimentin via its postsynaptic density 95/disc-large/zona occludens domains and in MDCK cells redistributes from filaments to the plasma membrane during the establishment of cell–cell contacts. RNA interference-mediated silencing of Scrib, vimentin, or both in MDCK cells results in defects in the polarization of the Golgi apparatus during cell migration. Concomitantly, wound healing is delayed due to the loss of directional movement. Furthermore, cell aggregation is dependent on both Scrib and vimentin. The similar phenotypes observed after silencing either Scrib or vimentin support a coordinated role for the two proteins in cell migration and aggregation. Interestingly, silencing of vimentin leads to an increased proteasomal degradation of Scrib. Thus, the upregulation of vimentin expression during epithelial to mesenchymal transitions may stabilize Scrib to promote directed cell migration.

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Pike, K. A., S. Kulkarni, and T. Pawson. "Immature T-cell clustering and efficient differentiation require the polarity protein Scribble." Proceedings of the National Academy of Sciences 108, no. 3 (December 28, 2010): 1116–21. http://dx.doi.org/10.1073/pnas.1018224108.

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Roh, Michael H., and Ben Margolis. "Composition and function of PDZ protein complexes during cell polarization." American Journal of Physiology-Renal Physiology 285, no. 3 (September 2003): F377—F387. http://dx.doi.org/10.1152/ajprenal.00086.2003.

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Complexes consisting of PDZ proteins have been implicated in a variety of cellular processes. In recent years, it has become increasingly clear that PDZ proteins play essential roles during the establishment of spatial asymmetry in various metazoan cell types such as epithelial cells. Epithelial cells possess asymmetry with respect to the apicobasal axis reflected by the differential distribution of proteins and lipids in the apical and basolateral surfaces. In Drosophila, three PDZ protein complexes have been shown to play crucial functions during the establishment of cell-cell adhesions and epithelial cell polarity: Bazooka/Dm-Par6/DaPKC, Crumbs/Stardust/Discs Lost, and Scribble/Discs Large/Lethal Giant Larvae. In this review, we focus primarily on our current knowledge of the localization and function of these complexes in Drosophila epithelia. We also discuss recent data that enhance our understanding of the homologous protein complexes and their roles during junctional assembly and polarization of mammalian epithelial cells.

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Ganguly, Indrani, Trudy F. C. Mackay, and Robert R. H. Anholt. "Scribble Is Essential for Olfactory Behavior in Drosophila melanogaster." Genetics 164, no. 4 (August 1, 2003): 1447–57. http://dx.doi.org/10.1093/genetics/164.4.1447.

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Abstract The ability to discriminate and respond to chemical signals from the environment is an almost universal prerequisite for survival. Here, we report that the scaffold protein Scribble is essential for odor-guided behavior in Drosophila. Previously, we identified a P-element insert line with generalized sexually dimorphic smell impairment, smi97B. We found that the transposon in this line is located between the predicted promoter region and the transcription initiation site of scrib. A deficiency in this region, Df(3R)Tl-X, and two scrib null alleles fail to complement the smell-impaired phenotype of smi97B. Wild-type behavior is restored by precise excision of the P element, scrib mRNA levels correspond with mutant and wild-type phenotypes, and introduction of a full-length scrib transgene in the smi97B mutant rescues the olfactory deficit. Expression of Scrib is widespread in olfactory organs and the central nervous system. Finally, alternative splicing of scrib generates transcripts that differ in the number of leucine-rich repeats and PDZ domains.

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Jarjour, Andrew A., Amanda Boyd, Lukas E. Dow, Rebecca K. Holloway, Sandra Goebbels, Patrick O. Humbert, Anna Williams, and Charles ffrench-Constant. "The Polarity Protein Scribble Regulates Myelination and Remyelination in the Central Nervous System." PLOS Biology 13, no. 3 (March 25, 2015): e1002107. http://dx.doi.org/10.1371/journal.pbio.1002107.

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Hendrick, Janina, Mirita Franz-Wachtel, Yvonne Moeller, Simone Schmid, Boris Macek, and Monilola A. Olayioye. "The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling." Journal of Cell Science 129, no. 19 (August 5, 2016): 3583–96. http://dx.doi.org/10.1242/jcs.190074.

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Hendrick, Janina, Mirita Franz-Wachtel, Yvonne Moeller, Simone Schmid, Boris Macek, and Monilola A. Olayioye. "The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling." Development 143, no. 20 (October 15, 2016): e1.2-e1.2. http://dx.doi.org/10.1242/dev.145417.

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Roche, John P., Mary C. Packard, Stephanie Moeckel-Cole, and Vivian Budnik. "Regulation of Synaptic Plasticity and Synaptic Vesicle Dynamics by the PDZ Protein Scribble." Journal of Neuroscience 22, no. 15 (August 1, 2002): 6471–79. http://dx.doi.org/10.1523/jneurosci.22-15-06471.2002.

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Qin, Yi, Christopher Capaldo, Barry M. Gumbiner, and Ian G. Macara. "The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin." Journal of Cell Biology 171, no. 6 (December 12, 2005): 1061–71. http://dx.doi.org/10.1083/jcb.200506094.

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Scribble (Scrib) is a conserved polarity protein required in Drosophila melanogaster for synaptic function, neuroblast differentiation, and epithelial polarization. It is also a tumor suppressor. In rodents, Scrib has been implicated in receptor recycling and planar polarity but not in apical/basal polarity. We now show that knockdown of Scrib disrupts adhesion between Madin–Darby canine kidney epithelial cells. As a consequence, the cells acquire a mesenchymal appearance, migrate more rapidly, and lose directionality. Although tight junction assembly is delayed, confluent monolayers remain polarized. These effects are independent of Rac activation or Scrib binding to βPIX. Rather, Scrib depletion disrupts E-cadherin–mediated cell–cell adhesion. The changes in morphology and migration are phenocopied by E-cadherin knockdown. Adhesion is partially rescued by expression of an E-cadherin–α-catenin fusion protein but not by E-cadherin–green fluorescent protein. These results suggest that Scrib stabilizes the coupling between E-cadherin and the catenins and are consistent with the idea that mammalian Scrib could behave as a tumor suppressor by regulating epithelial cell adhesion and migration.

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Troyanovsky, Regina B., Indrajyoti Indra, Rei Kato, Brian J. Mitchell, and Sergey M. Troyanovsky. "Basolateral protein Scribble binds phosphatase PP1 to establish a signaling network maintaining apicobasal polarity." Journal of Biological Chemistry 297, no. 5 (November 2021): 101289. http://dx.doi.org/10.1016/j.jbc.2021.101289.

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Cai, Pengfei, Yi Mu, Xianyu Piao, Nan Hou, Shuai Liu, Youhe Gao, Heng Wang, and Qijun Chen. "Discovery and Confirmation of Ligand Binding Specificities of the Schistosoma japonicum Polarity Protein Scribble." PLoS Neglected Tropical Diseases 8, no. 5 (May 1, 2014): e2837. http://dx.doi.org/10.1371/journal.pntd.0002837.

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Lin, Wan-Hsin, Yan W. Asmann, and Panos Z. Anastasiadis. "Expression of Polarity Genes in Human Cancer." Cancer Informatics 14s3 (January 2015): CIN.S18964. http://dx.doi.org/10.4137/cin.s18964.

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Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration. Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters. Here, we review the current understanding of polarity protein functions in epithelial homeostasis, as well as tumor formation and progression. As most previous studies focused on the function of single polarity proteins in simplified model systems, we used a genomics approach to systematically examine and identify the expression profiles of polarity genes in human cancer. The expression profiles of polarity genes were distinct in different human tissues and classified cancer types. Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered. In the case of Scribble, gene expression analysis indicated its common amplification and upregulation in human cancer, suggesting a tumor promoting function.

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Stucke, Volker M., Evy Timmerman, Joel Vandekerckhove, Kris Gevaert, and Alan Hall. "The MAGUK Protein MPP7 Binds to the Polarity Protein hDlg1 and Facilitates Epithelial Tight Junction Formation." Molecular Biology of the Cell 18, no. 5 (May 2007): 1744–55. http://dx.doi.org/10.1091/mbc.e06-11-0980.

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Three groups of evolutionarily conserved proteins have been implicated in the establishment of epithelial cell polarity: the apically-localized proteins of the Par (Par3-Par6-aPKC-Cdc42) and Crumbs groups (Crb3-PALS1-PATJ) and the basolaterally localized proteins of the Dlg group (Dlg1-Scribble-Lgl). During epithelial morphogenesis, these proteins participate in a complex network of interdependent interactions that define the position and functional organization of adherens junctions and tight junctions. However, the biochemical pathways through which they control polarity are poorly understood. In this study, we identify an interaction between endogenous hDlg1 and MPP7, a previously uncharacterized MAGUK-p55 subfamily member. We find that MPP7 targets to the lateral surface of epithelial cells via its L27N domain, through an interaction with hDlg1. Loss of either hDlg1 or MPP7 from epithelial Caco-2 cells results in a significant defect in the assembly and maintenance of functional tight junctions. We conclude that the formation of a complex between hDlg1 and MPP7 promotes epithelial cell polarity and tight junction formation.

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Li, Linxi, Ying Gao, Haiqi Chen, Tito Jesus, Elizabeth Tang, Nan Li, Qingquan Lian, Ren-shan Ge, and C. Yan Cheng. "Cell polarity, cell adhesion, and spermatogenesis: role of cytoskeletons." F1000Research 6 (August 25, 2017): 1565. http://dx.doi.org/10.12688/f1000research.11421.1.

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In the rat testis, studies have shown that cell polarity, in particular spermatid polarity, to support spermatogenesis is conferred by the coordinated efforts of the Par-, Crumbs-, and Scribble-based polarity complexes in the seminiferous epithelium. Furthermore, planar cell polarity (PCP) is conferred by PCP proteins such as Van Gogh-like 2 (Vangl2) in the testis. On the other hand, cell junctions at the Sertoli cell–spermatid (steps 8–19) interface are exclusively supported by adhesion protein complexes (for example, α6β1-integrin-laminin-α3,β3,γ3 and nectin-3-afadin) at the actin-rich apical ectoplasmic specialization (ES) since the apical ES is the only anchoring device in step 8–19 spermatids. For cell junctions at the Sertoli cell–cell interface, they are supported by adhesion complexes at the actin-based basal ES (for example, N-cadherin-β-catenin and nectin-2-afadin), tight junction (occludin-ZO-1 and claudin 11-ZO-1), and gap junction (connexin 43-plakophilin-2) and also intermediate filament-based desmosome (for example, desmoglein-2-desmocollin-2). In short, the testis-specific actin-rich anchoring device known as ES is crucial to support spermatid and Sertoli cell adhesion. Accumulating evidence has shown that the Par-, Crumbs-, and Scribble-based polarity complexes and the PCP Vangl2 are working in concert with actin- or microtubule-based cytoskeletons (or both) and these polarity (or PCP) protein complexes exert their effects through changes in the organization of the cytoskeletal elements across the seminiferous epithelium of adult rat testes. As such, there is an intimate relationship between cell polarity, cell adhesion, and cytoskeletal function in the testis. Herein, we critically evaluate these recent findings based on studies on different animal models. We also suggest some crucial future studies to be performed.

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Aikawa, Shizu, Jia Yuan, Amanda Dewar, Xiaofei Sun, and Sudhansu K. Dey. "Scribble promotes alveologenesis in the pregnant mammary gland for milk production." Reproduction 159, no. 6 (May 2020): 719–31. http://dx.doi.org/10.1530/rep-20-0108.

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Mammary glands are comprised of ducts and terminal lobules that form tree-like structures. Luminal epithelial cells in these lobules undergo differentiation into alveolar cells in pregnancy to support milk production. This study reveals that Scribble (SCRIB), a scaffold protein expressed in progesterone receptor (PGR)-positive cells, plays a critical role in mammary gland alveologenesis in mice. We conditionally deleted Scrib using a Pgr-Cre driver. PGR is heterogeneously expressed throughout the luminal epithelium. Scrib loss in mammary glands by Pgr-Cre (Scribf/fPgrCre/+) shows inefficient alveologenesis and terminal end bud (TEB)-like morphology during pregnancy, resulting in poor milk production and subsequent death of pups after delivery. The differentiation of PGR-positive epithelial cells into Elf5-expressing alveolar cells is defective in Scribf/fPgrCre/+ mice. These changes are reflected in reduced activation of JAK2 and PAK1, resulting in downregulation of pSTAT5, a critical transcriptional factor for alveologenesis. These results provide evidence that SCRIB impacts PGR-positive cell lineage during alveologenesis, which impacts milk production and the health of offspring.

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Riga, Amalia, Janine Cravo, Ruben Schmidt, Helena R. Pires, Victoria G. Castiglioni, Sander van den Heuvel, and Mike Boxem. "Caenorhabditis elegans LET-413 Scribble is essential in the epidermis for growth, viability, and directional outgrowth of epithelial seam cells." PLOS Genetics 17, no. 10 (October 21, 2021): e1009856. http://dx.doi.org/10.1371/journal.pgen.1009856.

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The conserved adapter protein Scribble (Scrib) plays essential roles in a variety of cellular processes, including polarity establishment, proliferation, and directed cell migration. While the mechanisms through which Scrib promotes epithelial polarity are beginning to be unraveled, its roles in other cellular processes including cell migration remain enigmatic. In C. elegans, the Scrib ortholog LET-413 is essential for apical–basal polarization and junction formation in embryonic epithelia. However, whether LET-413 is required for postembryonic development or plays a role in migratory events is not known. Here, we use inducible protein degradation to investigate the functioning of LET-413 in larval epithelia. We find that LET-413 is essential in the epidermal epithelium for growth, viability, and junction maintenance. In addition, we identify a novel role for LET-413 in the polarized outgrowth of the epidermal seam cells. These stem cell-like epithelial cells extend anterior and posterior directed apical protrusions in each larval stage to reconnect to their neighbors. We show that the role of LET-413 in seam cell outgrowth is likely mediated largely by the junctional component DLG-1 discs large, which we demonstrate is also essential for directed outgrowth of the seam cells. Our data uncover multiple essential functions for LET-413 in larval development and show that the polarized outgrowth of the epithelial seam cells is controlled by LET-413 Scribble and DLG-1 Discs large.

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Peng, Yaoming, Xiaoxia Liu, Zhixing Jin, Haiou Liu, and Congjian Xu. "Scribble downregulation in adenomyosis compromises endometrial stromal decidualization by decreasing FOXO1 expression." Human Reproduction 37, no. 1 (November 8, 2021): 93–108. http://dx.doi.org/10.1093/humrep/deab234.

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Abstract STUDY QUESTION Does Scribble (SCRIB) contribute to aberrant decidualization of endometrial stromal cells (ESC) in adenomyosis? SUMMARY ANSWER SCRIB knockdown impairs decidualization of ESC by decreasing Fork-head box O1A (FOXO1) expression through the protein kinase B (AKT) and atypical protein kinase C (aPKC) activated pathways. WHAT IS KNOWN ALREADY Stromal SCRIB is required for primary decidual zone formation and pregnancy success in mice. In our previous studies, decidualization was dampened in ESC isolated from adenomyosis patients, yet the underlying molecular mechanisms remain elusive. STUDY DESIGN, SIZE, DURATION Eutopic endometrium tissue samples from diffuse adenomyosis and non-adenomyosis patients in proliferative, early-secretory and mid-secretory phase (n = 10 per phase for each group) were explored. In parallel, in vitro decidualization studies were carried out in ESC isolated from non-adenomyosis women (n = 8). PARTICIPANTS/MATERIALS, SETTING, METHODS The endometrial SCRIB expression was analyzed using immunohistochemistry staining and western blot. Quantitative RT-PCR (qRT-PCR), western blot and immunofluorescence staining were used to explore the expression of SCRIB in ESC during in vitro decidualization. siRNA-mediated SCRIB knockdown followed by decidual markers expression analysis, flow cytometry for cell cycle analysis and phalloidin staining for morphological analysis were performed to examine the function of SCRIB in ESC decidualization. RNA-sequencing was performed to examine the SCRIB-mediated transcriptional changes in decidualized ESC (DSC). Rescue experiments using an AKT inhibitor MK2206 and aPKC inhibitor NSC37044 were used to investigate the signaling pathways through which could mediate SCRIB-regulated FOXO1 protein expression and ESC decidualization. MAIN RESULTS AND THE ROLE OF CHANCE We found that the expression of SCRIB in the mid-secretory phase eutopic endometrial stroma of adenomyosis patients was significantly lower than that of non-adenomyosis. SCRIB knockdown reduced the expression of decidual markers, abrogated the epithelioid-like morphological changes, inhibited the mesenchymal-to-epithelial transitions process and promoted the cell cycle progression of ESC during in vitro decidualization. SCRIB knockdown-induced decidualization defects were attributed to a decrease in expression of transcription factor FOXO1, known to regulate decidualization. Furthermore, we found that SCRIB knockdown induced the aberrant activation of AKT and aPKC, which led to FOXO1 phosphorylation and degradation. Rescue assay confirmed that restoring the expression of FOXO1 effectively reversed the decidualization defects and cell cycle progression caused by SCRIB knockdown. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION In this study, it was demonstrated that SCRIB knockdown mediated the activation of AKT and aPKC, contributing to FOXO1 degradation and aberrant decidualization, however, the molecular link between AKT and aPKC signaling was not determined, and still requires further exploration. WIDER IMPLICATIONS OF THE FINDINGS Our findings support the hypothesis that adenomyosis interferes with embryo implantation due to insufficient endometrial receptivity. Abnormal decidualization of the endometrial stroma may clarify the possible association between adenomyosis and infertility. Our findings may be clinically useful for counseling and treatment of infertile adenomyosis patients. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (82001523 and 82171639). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A.

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Khoury, Mark J., and David Bilder. "Distinct activities of Scrib module proteins organize epithelial polarity." Proceedings of the National Academy of Sciences 117, no. 21 (May 15, 2020): 11531–40. http://dx.doi.org/10.1073/pnas.1918462117.

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A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using theDrosophilafollicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein–protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.

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Kohsaka, Hiroshi, Etsuko Takasu, and Akinao Nose. "In vivo induction of postsynaptic molecular assembly by the cell adhesion molecule Fasciclin2." Journal of Cell Biology 179, no. 6 (December 10, 2007): 1289–300. http://dx.doi.org/10.1083/jcb.200705154.

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Cell adhesion molecules (CAMs) are thought to mediate interactions between innervating axons and their targets. However, such interactions have not been directly observed in vivo. In this paper, we study the function and dynamics of Fasciclin2 (Fas2), a homophilic CAM expressed both pre- and postsynaptically during neuromuscular synapse formation in Drosophila melanogaster. We apply live imaging of functional fluorescent fusion proteins expressed in muscles and find that Fas2 and Discs-Large (Dlg; a scaffolding protein known to bind Fas2) accumulate at the synaptic contact site soon after the arrival of the nerve. Genetic, deletion, and photobleaching analyses suggest that Fas2-mediated trans-synaptic adhesion is important for the postsynaptic accumulation of both Fas2 itself and Dlg. In fas2 mutants, many aspects of synapse formation appear normal; however, we see a reduction in the synaptic accumulation of Scribble (another scaffolding protein) and glutamate receptor subunits GluRIIA and GluRIIB. We propose that Fas2 mediates trans-synaptic adhesion, which contributes to postsynaptic molecular assembly at the onset of synaptogenesis.

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Nakagawa, Shunsuke, and Jon M. Huibregtse. "Human Scribble (Vartul) Is Targeted for Ubiquitin-Mediated Degradation by the High-Risk Papillomavirus E6 Proteins and the E6AP Ubiquitin-Protein Ligase." Molecular and Cellular Biology 20, no. 21 (November 1, 2000): 8244–53. http://dx.doi.org/10.1128/mcb.20.21.8244-8253.2000.

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ABSTRACT The high-risk human papillomavirus (HPV) E6 proteins stimulate the ubiquitination and degradation of p53, dependent on the E6AP ubiquitin-protein ligase. Other proteins have also been shown to be targeted for degradation by E6, including hDlg, the human homolog of the Drosophila melanogaster Discs large (Dlg) tumor suppressor. We show here that the human homolog of theDrosophila Scribble (Vartul) (hScrib) tumor suppressor protein is also targeted for ubiquitination by the E6-E6AP complex in vitro and that expression of E6 induces degradation of hScrib in vivo. Characterization of the E6AP-E6-hScrib complex indicated that hScrib binds directly to E6 and that the binding is mediated by the PDZ domains of hScrib and a carboxyl-terminal epitope conserved among the high-risk HPV E6 proteins. Green fluorescent protein-hScrib was localized to the periphery of MDCK cells, where it colocalized with ZO-1, a component of tight junctions. E6 expression resulted in loss of integrity of tight junctions, as measured by ZO-1 localization, and this effect was dependent on the PDZ binding epitope of E6. Thus, the high-risk HPV E6 proteins induce the degradation of the human homologs of two Drosophila PDZ domain-containing tumor suppressor proteins, hDlg and hScrib, both of which are associated with cell junction complexes. The fact that Scrib/Vart and Dlg appear to cooperate in a pathway that controls Drosophila epithelial cell growth suggests that the combined targeting of hScrib and hDlg is an important component of the biologic activity of high-risk HPV E6 proteins.

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Zeitler, Jennifer, Cynthia P. Hsu, Heather Dionne, and David Bilder. "Domains controlling cell polarity and proliferation in the Drosophila tumor suppressor Scribble." Journal of Cell Biology 167, no. 6 (December 20, 2004): 1137–46. http://dx.doi.org/10.1083/jcb.200407158.

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Cell polarity and cell proliferation can be coupled in animal tissues, but how they are coupled is not understood. In Drosophila imaginal discs, loss of the neoplastic tumor suppressor gene scribble (scrib), which encodes a multidomain scaffolding protein, disrupts epithelial organization and also causes unchecked proliferation. Using an allelic series of mutations along with rescuing transgenes, we have identified domain requirements for polarity, proliferation control, and other Scrib functions. The leucine-rich repeats (LRR) tether Scrib to the plasma membrane, are both necessary and sufficient to organize a polarized epithelial monolayer, and are required for all proliferation control. The PDZ domains, which recruit the LRR to the junctional complex, are dispensable for overall epithelial organization. PDZ domain absence leads to mild polarity defects accompanied by moderate overproliferation, but the PDZ domains alone are insufficient to provide any Scrib function in mutant discs. We suggest a model in which Scrib, via the activity of the LRR, governs proliferation primarily by regulating apicobasal polarity.

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Albertson, R. "Scribble protein domain mapping reveals a multistep localization mechanism and domains necessary for establishing cortical polarity." Journal of Cell Science 117, no. 25 (December 1, 2004): 6061–70. http://dx.doi.org/10.1242/jcs.01525.

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Mathew, Dennis, L. Sian Gramates, Mary Packard, Ulrich Thomas, David Bilder, Norbert Perrimon, Michael Gorczyca, and Vivian Budnik. "Recruitment of Scribble to the Synaptic Scaffolding Complex Requires GUK-holder, a Novel DLG Binding Protein." Current Biology 12, no. 7 (April 2002): 531–39. http://dx.doi.org/10.1016/s0960-9822(02)00758-3.

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Feigin, Michael E., S. Dipikaa Akshinthala, Kiyomi Araki, Avi Z. Rosenberg, Lakshmi B. Muthuswamy, Bernard Martin, Brian D. Lehmann, et al. "Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer." Cancer Research 74, no. 11 (March 24, 2014): 3180–94. http://dx.doi.org/10.1158/0008-5472.can-13-3415.

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Chevalier, Marc, Laura Cardoit, Maïté Moreau, Nathalie Sans, Mireille Montcouquiol, John Simmers, and Muriel Thoby-Brisson. "The embryonic development of hindbrain respiratory networks is unaffected by mutation of the planar polarity protein Scribble." Neuroscience 357 (August 2017): 160–71. http://dx.doi.org/10.1016/j.neuroscience.2017.05.046.

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Werme, Karin, Michael Wigerius, and Magnus Johansson. "Tick-borne encephalitis virus NS5 associates with membrane protein scribble and impairs interferon-stimulated JAK-STAT signalling." Cellular Microbiology 10, no. 3 (March 2008): 696–712. http://dx.doi.org/10.1111/j.1462-5822.2007.01076.x.

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Moreau, Maïté M., Susanna Pietropaolo, Jérôme Ezan, Benjamin J. A. Robert, Sylvain Miraux, Marlène Maître, Yoon Cho, Wim E. Crusio, Mireille Montcouquiol, and Nathalie Sans. "Scribble Controls Social Motivation Behavior through the Regulation of the ERK/Mnk1 Pathway." Cells 11, no. 10 (May 10, 2022): 1601. http://dx.doi.org/10.3390/cells11101601.

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Social behavior is a basic domain affected by several neurodevelopmental disorders, including ASD and a heterogeneous set of neuropsychiatric disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of neural tube defect, found at high frequencies in autistic patients, as well as other congenital anomalies. The deletions and mutations of the 8q24.3 region encompassing SCRIB are also associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and relevant social phenotypes has not been fully investigated. Hence, we show that Scribcrc/+ mice, carrying a mutated version of Scrib, displayed reduced social motivation behavior and social habituation, while other behavioral domains were unaltered. Social deficits were associated with the upregulation of ERK phosphorylation, together with increased c-Fos activity. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a link between polarity genes, social behaviors and hippocampal functionality and suggest a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway in underlying social motivation behavior, thus supporting its relevance as a therapeutic target.

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Schürmann, Christoph, Franziska L. Dienst, Katalin Pálfi, Andrea E. Vasconez, James A. Oo, ShengPeng Wang, Giulia K. Buchmann, et al. "The polarity protein Scrib limits atherosclerosis development in mice." Cardiovascular Research 115, no. 14 (April 5, 2019): 1963–74. http://dx.doi.org/10.1093/cvr/cvz093.

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Abstract Aims The protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized; however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions. Methods and results Tamoxifen-induced Scrib-knockout mice were crossed with ApoE−/− knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes. Conclusions By maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.

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Zelhof, Andrew C., Hong Bao, Robert W. Hardy, Azam Razzaq, Bing Zhang, and Chris Q. Doe. "DrosophilaAmphiphysin is implicated in protein localization and membrane morphogenesis but not in synaptic vesicle endocytosis." Development 128, no. 24 (December 15, 2001): 5005–15. http://dx.doi.org/10.1242/dev.128.24.5005.

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Amphiphysin family members are implicated in synaptic vesicle endocytosis, actin localization and one isoform is an autoantigen in neurological autoimmune disorder; however, there has been no genetic analysis of Amphiphysin function in higher eukaryotes. We show that Drosophila Amphiphysin is localized to actin-rich membrane domains in many cell types, including apical epithelial membranes, the intricately folded apical rhabdomere membranes of photoreceptor neurons and the postsynaptic density of glutamatergic neuromuscular junctions. Flies that lack all Amphiphysin function are viable, lack any observable endocytic defects, but have abnormal localization of the postsynaptic proteins Discs large, Lethal giant larvae and Scribble, altered synaptic physiology, and behavioral defects. Misexpression of Amphiphysin outside its normal membrane domain in photoreceptor neurons results in striking morphological defects. The strong misexpression phenotype coupled with the mild mutant and lack of phenotypes suggests that Amphiphysin acts redundantly with other proteins to organize specialized membrane domains within a diverse array of cell types.

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Kundu, Somanath, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, and Mariano S. Viapiano. "Abstract 3167: The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3167. http://dx.doi.org/10.1158/1538-7445.am2022-3167.

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Abstract Proteins complexes that maintain the apico-basal polarity of epithelial cells and organize cell-signaling domains are necessary for normal tissue organization and therefore regarded as tumor suppressors. Accordingly, the scaffolding proteins that form the Scribble polarity complex (SCRIB, LLGL1, and DLG members) are usually downregulated in cancer, in particular in highly aggressive or invasive tumors. Because gliomas arise from non-epithelial precursors that are likely motile before transformation, the expression and functions of these scaffolding proteins in malignant brain tumors has remained almost entirely unexplored. Surprisingly, we have found that one member of the DLG family, DLG5, is highly upregulated in malignant gliomas compared to other solid tumors. Indeed, DLG5 was the predominant DLG member found in all molecular subtypes of glioblastoma (GBM). Knockdown of DLG5 reduced the viability, invasiveness, and self-renewal of GBM stem cells belonging to the proneural and mesenchymal molecular subtypes. As a result, intracranial tumors defficient in DLG5 were smaller and less proliferative than controls, resulting in extended animal survival. At the molecular level, DLG5 knockdown decreased the expression of stemness-related genes (SOX2, NANOG, POU5F1) but increased the expression of LLGL1, a component of the Scribble complex that is associated with neural precursor differentiation. These changes were accompanied by downregulation of Sonic Hedgehog (SHh) signaling, both in vitro and in vivo, which drives GBM cell stemness and proliferation. Moreover, DLG5-deficient GBM stem cells became insensitive to exogenous SHh and were unable to upregulate Gli1 or increase cell invasion in presence of added SHh, compared to control cells. We further confirmed that DLG5 downregulation increased the ubiquitination of Gli1-containing complexes as well as Gli1 proteasomal degradation, providing a suitable mechanism for the loss of SHh signaling and tumor stemness. These results describe for the first time the expression of a DLG family member in malignant gliomas and reveal a novel, polarity-independent, pro-tumoral function of DLG5, which differs from its proposed tumor-suppressor role in other solid tumors. Citation Format: Somanath Kundu, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, Mariano S. Viapiano. The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3167.

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Nakagawa, Shunsuke, and Jon M. Huibregtse. "Human Scribble (Vartul) Is Targeted for Ubiquitin-Mediated Degradation by the High-Risk Papillomavirus E6 Proteins and the E6AP Ubiquitin-Protein Ligase." Molecular and Cellular Biology 20, no. 21 (2000): 8244–53. http://dx.doi.org/10.1128/.20.21.8244-8253.2000.

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Wu, Xiaoyi, Weiwen Zuo, Haiou Liu, Zehua Wang, and Congjian Xu. "Decreased expression of cell polarity protein Scribble correlated with altered subcellular localization of the Crumbs homologue 3 protein in human adenomyotic endometrial cells." Journal of Obstetrics and Gynaecology Research 45, no. 6 (March 25, 2019): 1148–59. http://dx.doi.org/10.1111/jog.13952.

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Christensen, Inga Baasch, Esben Nees Mogensen, Helle Hasager Damkier, and Jeppe Praetorius. "Choroid plexus epithelial cells express the adhesion protein P-cadherin at cell-cell contacts and syntaxin-4 in the luminal membrane domain." American Journal of Physiology-Cell Physiology 314, no. 5 (May 1, 2018): C519—C533. http://dx.doi.org/10.1152/ajpcell.00305.2017.

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The choroid plexus epithelial cells (CPECs) belong to a small group of polarized cells, where the Na+-K+-ATPase is expressed in the luminal membrane. The basic polarity of the cells is, therefore, still debated. We investigated the subcellular distribution of an array of proteins known to play fundamental roles either in establishing and maintaining basic cell polarity or in the polarized delivery and recycling of plasma membrane proteins. Immunofluorescence histochemical analysis was applied to determine the subcellular localization of apical and basolateral membrane determinants. Mass spectrometry analysis of CPECs isolated by fluorescence-activated cell sorting was applied to determine the expression of specific forms of the proteins. CPECs mainly express the cell-adhesive P-cadherin, which is localized to the lateral membranes. Proteins belonging to the Crumbs and partitioning defective (Par) protein complexes were all localized to the luminal membrane domain. Par-1 and the Scribble complex were localized to the basolateral membrane domain. Lethal(2) giant larvae homolog 2 (Lgl2) labeling was preferentially observed in the luminal membrane domain. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) was immunolocalized to the basolateral membrane domain, while phosphatidylinositol 4,5-bisphosphate (PIP2) staining was most prominent in the luminal membrane domain along with the PIP3 phosphatase, Pten. The apical target-SNARE syntaxin-3 and the basolateral target-SNARE syntaxin-4 were both localized to the apical membrane domain in CPECs, which lack cellular expression of the clathrin adaptor protein AP-1B for basolateral protein recycling. In conclusion, the CPECs are conventionally polarized, but express P-cadherin at cell-cell contacts, and Lgl2 and syntaxin-4 in the luminal plasma membrane domain.

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Troyanovsky, Regina B., Alina P. Sergeeva, Indrajyoti Indra, Chi-Shuo Chen, Rei Kato, Lawrence Shapiro, Barry Honig, and Sergey M. Troyanovsky. "Sorting of cadherin–catenin-associated proteins into individual clusters." Proceedings of the National Academy of Sciences 118, no. 29 (July 16, 2021): e2105550118. http://dx.doi.org/10.1073/pnas.2105550118.

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The cytoplasmic tails of classical cadherins form a multiprotein cadherin–catenin complex (CCC) that constitutes the major structural unit of adherens junctions (AJs). The CCC in AJs forms junctional clusters, “E clusters,” driven by cis and trans interactions in the cadherin ectodomain and stabilized by α-catenin–actin interactions. Additional proteins are known to bind to the cytoplasmic region of the CCC. Here, we analyze how these CCC-associated proteins (CAPs) integrate into cadherin clusters and how they affect the clustering process. Using a cross-linking approach coupled with mass spectrometry, we found that the majority of CAPs, including the force-sensing protein vinculin, interact with CCCs outside of AJs. Accordingly, structural modeling shows that there is not enough space for CAPs the size of vinculin to integrate into E clusters. Using two CAPs, scribble and erbin, as examples, we provide evidence that these proteins form separate clusters, which we term “C clusters.” As proof of principle, we show, by using cadherin ectodomain monoclonal antibodies (mAbs), that mAb-bound E-cadherin forms separate clusters that undergo trans interactions. Taken together, our data suggest that, in addition to its role in cell–cell adhesion, CAP-driven CCC clustering serves to organize cytoplasmic proteins into distinct domains that may synchronize signaling networks of neighboring cells within tissues.

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Journal articles on the topic 'Scribble protein'

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