Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling

he Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2-ZO-2 complex could represent a target for cancer therapy

Is it worth reorganising cancer services on the basis of multidisciplinary teams (MDTs)? A systematic review of the objectives and organisation of MDTs and their impact on patient outcomes

Multidisciplinary teams (MDTs) are considered the gold standard of cancer care in many healthcare systems, but a clear definition of their format, scope of practice and operational criteria is still lacking. The aims of this review were to assess the impact of MDTs on patient outcomes in cancer care and identify their objectives, organisation and ability to engage patients in their care. We conducted a systematic review of the literature in the Medline database. Fifty-one peer-reviewed papers were selected from November 2005 to June 2012. MDTs resulted in better clinical and process outcomes for cancer patients, with evidence of improved survival among colorectal, head and neck, breast, oesophageal and lung cancer patients in the study period. Also, it was observed that MDTs have been associated with changes in clinical diagnostic and treatment decision-making with respect to urological, pancreatic, gastro-oesophageal, breast, melanoma, bladder, colorectal, prostate, head and neck and gynaecological cancer. Evidence is consistent in showing positive consequences for patients' management in multiple dimensions, which should encourage the development of structured multidisciplinary care, minimum standards and exchange of best practices

Is it worth reorganising cancer services on the basis of multidisciplinary teams (MDTs)? A systematic review of the objectives and organisation of MDTs and their impact on patient outcomes

Multidisciplinary teams (MDTs) are considered the gold standard of cancer care in many healthcare systems, but a clear definition of their format, scope of practice and operational criteria is still lacking. The aims of this review were to assess the impact of MDTs on patient outcomes in cancer care and identify their objectives, organisation and ability to engage patients in their care. We conducted a systematic review of the literature in the Medline database. Fifty-one peer-reviewed papers were selected from November 2005 to June 2012. MDTs resulted in better clinical and process outcomes for cancer patients, with evidence of improved survival among colorectal, head and neck, breast, oesophageal and lung cancer patients in the study period. Also, it was observed that MDTs have been associated with changes in clinical diagnostic and treatment decision-making with respect to urological, pancreatic, gastro-oesophageal, breast, melanoma, bladder, colorectal, prostate, head and neck and gynaecological cancer. Evidence is consistent in showing positive consequences for patients' management in multiple dimensions, which should encourage the development of structured multidisciplinary care, minimum standards and exchange of best practices

TAZ interacts with zonula occludens-1 and-2 proteins in a PDZ-1 dependent manner

AbstractThe transcriptional coactivator TAZ recognizes L/PPxY motifs in transcription factors like Runx1/2 through its WW domain. We show that the first PDZ domain of zona occludens-1 (ZO-1) and 2 (ZO-2) interacts with the carboxy-terminal PDZ binding motif of TAZ. Deletion of this motif abrogates binding. ZO-2 colocalizes with TAZ in the nucleus of MDCK cells and ZO-2 expression alters TAZ localization in human embryonic kidney cells. Luciferase assays demonstrate ZO-2 inhibition of TAZ-mediated transactivation. We propose that zonula occludens is a negative regulator of TAZ and suggest that selected tight junction proteins control nuclear translocation and activity of TAZ.Structured summaryMINT-7994937: ZO-2 (uniprotkb:Q95168) binds (MI:0407) to TAZ (uniprotkb:Q9EPK5) by pull down (MI:0096) MINT-7994900, MINT-7994835, MINT-7994885: ZO-1 (uniprotkb:Q07157) physically interacts (MI:0915) with TAZ (uniprotkb:Q9EPK5) by pull down (MI:0096) MINT-7995020: ZO-2 (uniprotkb:Q9UDY2) and TAZ (uniprotkb:Q9GZV5) colocalize (MI:0403) by fluorescence microscopy (MI:0416)MINT-7994953: ZO-1 (uniprotkb:Q07157) binds (MI:0407) to TAZ (uniprotkb:Q9EPK5) by pull down (MI:0096) MINT-7994970: TAZ (uniprotkb:73990382) and ZO-2 (uniprotkb:Q95168) colocalize (MI:0403) by fluorescence microscopy (MI:0416) MINT-7994867: TAZ (uniprotkb:Q9EPK5) physically interacts (MI:0915) with ZO-2 (uniprotkb:Q9UDY2) by pull down (MI:0096) MINT-7994988: TAZ (uniprotkb:Q9GZV5) and ZO-1 (uniprotkb:Q07157) colocalize (MI:0403) by fluorescence microscopy (MI:0416) MINT-7994999: TAZ (uniprotkb:Q9EPK5) and ZO-2 (uniprotkb:Q95168) colocalize (MI:0403) by fluorescence microscopy (MI:0416) MINT-7994922, MINT-7994853: ZO-2 (uniprotkb:Q95168) physically interacts (MI:0915) with TAZ (uniprotkb:Q9EPK5) by pull down (MI:0096

The Tandem PDZ Protein Syntenin Interacts with the Aminoacyl tRNA Synthetase Complex in a Lysyl-tRNA Synthetase-Dependent Manner

Syntenin-1 is a tandem PDZ protein that binds a diverse array of signaling molecules that are often associated with cell adhesion and intracellular trafficking. With the use of a MS-based functional proteornics approach, we identified several members of the aminoacyl-tRNA synthetase macromolecular (ARS) complex in a syntenin-1 pull down assay. Interaction of these proteins with syntenin-1 was confirmed by co-immunoprecipitation from cultured cells. We demonstrate a direct interaction of syntenin-1 with lysyl-tRNA synthetase (KRS), which contains a PDZ binding motif at its C-terminus. This motif is important for the interaction of the entire complex with syntenin-1. A point mutation in the PDZ2 domain of syntenin-1 abrogates interaction with KRS. As a result, other components of the ARS complex no longer co-immunoprecipitate with syntenin-1. We further show that syntenin-1 regulates KRS activity. These findings suggest that syntenin-1 is an adaptor modulating the activity of KRS

The PDZ2 domain of zonula occludens-1 and-2 is a phosphoinositide binding domain

Zonula occludens proteins (ZO) are postsynaptic density protein-95 discs large-zonula occludens (PDZ) domain-containing proteins that play a fundamental role in the assembly of tight junctions and establishment of cell polarity. Here, we show that the second PDZ domain of ZO-1 and ZO-2 binds phosphoinositides (PtdInsP) and we identified critical residues involved in the interaction. Furthermore, peptide and PtdInsP binding of ZO PDZ2 domains are mutually exclusive. Although lipid binding does not seem to be required for plasma membrane localisation of ZO-1, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P (2)) binding to the PDZ2 domain of ZO-2 regulates ZO-2 recruitment to nuclear speckles. Knockdown of ZO-2 expression disrupts speckle morphology, indicating that ZO-2 might play an active role in formation and stabilisation of these subnuclear structures. This study shows for the first time that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus

Tobacco products in the European Union Common Entry Gate (EU-CEG): A tool for monitoring the EU tobacco products directive.

INTRODUCTION: Under the European Union (EU) Tobacco Products Directive (2014/40/EU) (TPD), manufacturers and importers of tobacco products are required to report information to the European Commission (EC) and Member States (MS) on products intended to be placed on the market. We describe the distribution of notifications to the EU Common Entry Gate (EU-CEG) and identify key fields for improvement on reporting cigarettes or roll-your-own (RYO) tobacco. METHODS: A cross-sectional analysis of secondary data reported in the EU-CEG was conducted for tobacco products notified within EU-CEG between June 2016 and October 2019 for 12 EU MS. Analysis of compliance to specific regulations for priority additives that refer to cigarettes and RYO was conducted for 10 EU countries. RESULTS: Overall, 39170 tobacco products were notified. This included 16762 (42.8%) notifications of cigars, followed by cigarettes 11242 (28.7 %), waterpipes 3291 (8.4%), cigarillos (n=1783), pipe (n=1715), RYO (n=1635), chewing tobacco (n=1021), novel tobacco products (n=839), herbal products for smoking (n=535), other (n=258), nasal (n=74) and oral tobacco (n=15). In cigarettes and RYO tobacco products, the proportion of ingredients notified in all countries that contained an unknown Chemical Abstract Services (CAS) number was 3.8% and 2.1%, respectively. The proportion of underreporting flagging of priority additives ranged from 15.9% in Malta to 41.3% in Lithuania, the mean proportion of underreporting of the variable ‘priority additive’ for the 10 countries together was 24.7%. CONCLUSIONS: In the EU-CEG data base, for the period of analysis, a significant number of product notifications took place while large variations in the number of types of tobacco products notified across EU countries was noted. The timely monitoring of these data is needed so that products non-compliant within the EU-CEG system are assessed