scholarly journals Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis

Cell Reports ◽  
2021 ◽  
Vol 36 (8) ◽  
pp. 109596
Author(s):  
Yu Wang ◽  
Yuwen Zhu ◽  
Yuan Gu ◽  
Mingyue Ma ◽  
Yebin Wang ◽  
...  
Keyword(s):  
Full Activation

scholarly journals Differential Role of Threonine and Tyrosine Phosphorylation in the Activation and Activity of the Yeast MAPK Slt2

2021 ◽  
Vol 22 (3) ◽  
pp. 1110
Author(s):  
Gema González-Rubio ◽  
Ángela Sellers-Moya ◽  
Humberto Martín ◽  
María Molina
Keyword(s):  
Cell Wall ◽  
Biological Activity ◽  
Biological Significance ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
High Increase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Full Activation

The Mitogen-Activated Protein Kinase (MAPK) Slt2 is central to signaling through the yeast Cell Wall Integrity (CWI) pathway. MAPKs are regulated by phosphorylation at both the threonine and tyrosine of the conserved TXY motif within the activation loop (T190/Y192 in Slt2). Since phosphorylation at both sites results in the full activation of MAPKs, signaling through MAPK pathways is monitored with antibodies that detect dually phosphorylated forms. However, most of these antibodies also recognize monophosphorylated species, whose relative abundance and functionality are diverse. By using different phosphospecific antibodies and phosphate-affinity (Phos-tag) analysis on distinct Slt2 mutants, we determined that Y192- and T190-monophosphorylated species coexist with biphosphorylated Slt2, although most of the Slt2 pool remains unphosphorylated following stress. Among the monophosphorylated forms, only T190 exhibited biological activity. Upon stimulation, Slt2 is first phosphorylated at Y192, mainly by the MAPKK Mkk1, and this phosphorylation is important for the subsequent T190 phosphorylation. Similarly, dephosphorylation of Slt2 by the Dual Specificity Phosphatase (DSP) Msg5 is ordered, with dephosphorylation of T190 depending on previous Y192 dephosphorylation. Whereas Y192 phosphorylation enhances the Slt2 catalytic activity, T190 is essential for this activity. The conserved T195 residue is also critical for Slt2 functionality. Mutations that abolish the activity of Slt2 result in a high increase in inactive Y192-monophosphorylated Slt2. The coexistence of different Slt2 phosphoforms with diverse biological significance highlights the importance of the precise detection of the Slt2 phosphorylation status.

scholarly journals Activation of the Kexin from Schizosaccharomyces pombeRequires Internal Cleavage of Its Initially Cleaved Prosequence

1998 ◽  
Vol 18 (1) ◽  
pp. 400-408 ◽  
Author(s):  
Dale Powner ◽  
John Davey
Keyword(s):  
Cleavage Site ◽  
Secretory Pathway ◽  
Catalytic Domain ◽  
Activation Process ◽  
Processing Enzymes ◽  
Free Translation ◽  
A Cell ◽  
Internal Site ◽  
Primary Cleavage ◽  
Full Activation

ABSTRACT Members of the kexin family of processing enzymes are responsible for the cleavage of many proproteins during their transport through the secretory pathway. The enzymes themselves are made as inactive precursors, and we investigated the activation process by studying the maturation of Krp1, a kexin from the fission yeastSchizosaccharomyces pombe. Using a cell-free translation-translocation system prepared from Xenopuseggs, we found that Krp1 is made as a preproprotein that loses the presequence during translocation into the endoplasmic reticulum. The prosequence is also rapidly cleaved in a reaction that is autocatalytic and probably intramolecular and is inhibited by disruption of the P domain. Prosequence cleavage normally occurs at Arg-Tyr-Lys-Arg102↓ (primary cleavage site) but can occur at Lys-Arg82 (internal cleavage site) and/or Trp-Arg99 when the basic residues are removed from the primary site. Cleavage of the prosequence is necessary but not sufficient for activation, and Krp1 is initially unable to process substrates presented in trans. Full activation is achieved after further incubation in the extract and is coincident with the addition of O-linked sugars. O glycosylation is not, however, essential for activity, and the crucial event appears to be cleavage of the initially cleaved prosequence at the internal site. Our results are consistent with a model in which the cleaved prosequence remains noncovalently associated with the catalytic domain and acts as an autoinhibitor of the enzyme. Inhibition is then relieved by a second (internal) cleavage of the inhibitory prosequence. Further support for this model is provided by our finding that overexpression of a Krp1 prosequence lacking a cleavable internal site dramatically reduced the growth rate of otherwise wild-type S. pombecells, an effect that was not seen after overexpression of the normal, internally cleavable, prosequence or prosequences that lack the Lys-Arg102 residues.

RPD3 encodes a second factor required to achieve maximum positive and negative transcriptional states in Saccharomyces cerevisiae

1991 ◽  
Vol 11 (12) ◽  
pp. 6317-6327 ◽  
Author(s):  
M Vidal ◽  
R F Gaber
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Target Genes ◽  
Current Data ◽  
Regulatory Function ◽  
Fourfold Increase ◽  
Recessive Mutations ◽  
Activation Of Transcription ◽  
Transcriptional Regulatory ◽  
Low Levels ◽  
Full Activation

In Saccharomyces cerevisiae, TRK1 and TRK2 encode the high- and low-affinity K+ transporters, respectively. In cells containing a deletion of TRK1, transcription levels of TRK2 are extremely low and are limiting for growth in media containing low levels of K+ (Trk- phenotype). Recessive mutations in RPD1 and RPD3 suppress the TRK2, conferring an approximately fourfold increase in transcription. rpd3 mutations confer pleiotropic phenotypes, including (i) mating defects, (ii) hypersensitivity to cycloheximide, (iii) inability to sporulate as homozygous diploids, and (iv) constitutive derepression of acid phosphatase. RPD3 was cloned and is predicted to encode a 48-kDa protein with no extensive similarity to proteins contained in current data bases. Deletion of RPD3 is not lethal but confers phenotypes identical to those caused by spontaneous mutations. RPD3 is required for both full repression and full activation of transcription of target genes including PHO5, STE6, and TY2. RPD3 is the second gene required for this function, since RPD1 is also required. The effects of mutations in RPD1 and RPD3 are not additive, suggesting that these genes are involved in the same transcriptional regulatory function or pathway.

scholarly journals Interdependence of Activation at rhaSR by Cyclic AMP Receptor Protein, the RNA Polymerase Alpha Subunit C-Terminal Domain, and RhaR

2000 ◽  
Vol 182 (23) ◽  
pp. 6774-6782 ◽  
Author(s):  
Carolyn C. Holcroft ◽  
Susan M. Egan
Keyword(s):  
Cyclic Amp ◽  
Rna Polymerase ◽  
Synergistic Effects ◽  
Receptor Protein ◽  
Mobility Shift ◽  
Α Subunit ◽  
Subunit C ◽  
Cyclic Amp Receptor Protein ◽  
Terminal Domain ◽  
Full Activation

ABSTRACT The Escherichia coli rhaSR operon encodes two AraC family transcription activators, RhaS and RhaR, and is activated by RhaR in the presence of l-rhamnose. β-Galactosidase assays of various rhaS-lacZ promoter fusions combined with mobility shift assays indicated that a cyclic AMP receptor protein (CRP) site located at −111.5 is also required for full activation of rhaSR expression. To address the mechanisms of activation by CRP and the RNA polymerase α-subunit C-terminal domain (α-CTD) at rhaSR, we tested the effects of alanine substitutions in CRP activating regions 1 and 2, overexpression of a truncated version of α (α-Δ235), and alanine substitutions throughout α-CTD. We found that DNA-contacting residues in α-CTD are required for full activation, and for simplicity, we discuss α-CTD as a third activator of rhaSR. CRP and RhaR could each partially activate transcription in the absence of the other two activators, and α-CTD was not capable of activation alone. In the case of CRP, this suggests that this activation involves neither an α-CTD interaction nor cooperative binding with RhaR, while in the case of RhaR, this suggests the likelihood of direct interactions with core RNA polymerase. We also found that CRP, RhaR, and α-CTD each have synergistic effects on activation by the others, suggesting direct or indirect interactions among all three. We have some evidence that the α-CTD–CRP and α-CTD–RhaR interactions might be direct. The magnitude of the synergistic effects was usually greater with just two activators than with all three, suggesting possible redundancies in the mechanisms of activation by CRP, α-CTD, and RhaR.

scholarly journals The mechanism of full activation of tumor suppressor PTEN at the phosphatidylinositol-enriched membrane

2021 ◽  
Author(s):  
Hyunbum Jang ◽  
Iris Nira Smith ◽  
Charis Eng ◽  
Ruth Nussinov
Keyword(s):  
Drug Discovery ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Full Length ◽  
Detailed Mechanism ◽  
Explicit Solvent ◽  
Signaling Lipids ◽  
Cell Growth And Proliferation ◽  
First Time ◽  
Full Activation

AbstractTumor suppressor PTEN dephosphorylates signaling lipid PIP3 produced by PI3Ks. Abundant PIP3 promotes cell growth and proliferation. PTEN is the second most highly mutated protein in cancer and is drugless. The detailed mechanism at the membrane of this pivotal phosphatase is unknown hindering understanding and drug discovery. Here for the first time, exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane, its interaction with membranes composed of zwitterionic phosphatidylcholine and anionic phosphatidylserine and phosphatidylinositol, including signaling lipids PIP2 and PIP3, and moving away from the zwitterionic and getting absorbed onto the anionic membrane that harbors the PIP3. PIP3 then allosterically unfolds the N-terminal PIP2 binding domain, translocating it to the membrane where its polybasic motif interacts with PIP2, localizing on microdomains enriched in signaling lipids, as PI3K does. Finally, we determined PTEN catalytic action at the membrane, all in line with available experimental observations.

scholarly journals The potential of e-ticketing for public transport planning: the Piedmont region case study

2016 ◽  
Author(s):  
Maurizio Arnone
Keyword(s):  
Performance Indicators ◽  
Load Factor ◽  
User Mobility ◽  
Mobility Patterns ◽  
Trace Back ◽  
Travel Diary ◽  
Full Activation ◽  
Piedmont Region

In the Piedmont region (Italy) the electronic ticketing system called BIP, is currently active across much of its territory, and thedata collected in the Province of Cuneo since the full activation of the system (2014) provide today a sound source ofinformation. Two different travel documents are available, travel passes and pay-per-use, with different validation rules: check-inonly for travel passes and check-in and check-out for pay-per-use. Data produced by this electronic ticketing system employingsmart cards allow to perform a detailed analysis of each user’s behaviour, and calculate time and space distributions of eachpassenger trip. In detail, data originating from smart card transactions allow to trace back the trip chains, establish journey originsand destinations, and produce a “travel diary” for each passenger. Based on this data, performance indicators (i.e. load factor) aswell as user mobility patterns and origin-destination matrices can be calculated in an automated and reliable way. This articlepresents a methodology for assessing the quality of the data collected when information about boarding and alighting stops isavailable from the (on board) validation system. It also presents an algorithm to assign a destination for each trip where only theboarding information is available. In the case study of the Province of Cuneo, it was found that 91% of the pay-per-use journeydata are reliable and can be used for further analysis, whereas with the use of the proposed algorithm it was possible to estimatethe destinations for 82% of the travel pass trips.DOI: http://dx.doi.org/10.4995/CIT2016.2016.1999

scholarly journals Anion channel SLAH3 is a regulatory target of chitin receptor-associated kinase PBL27 in microbial stomatal closure

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yi Liu ◽  
Tobias Maierhofer ◽  
Katarzyna Rybak ◽  
Jan Sklenar ◽  
Andy Breakspear ◽  
...  
Keyword(s):  
Stomatal Closure ◽  
Anion Channel ◽  
Anion Channels ◽  
Slow Type ◽  
Leaf Level ◽  
Short Signal ◽  
Molecular Patterns ◽  
Fungal Immunity ◽  
Anti Fungal ◽  
Full Activation

In plants, antimicrobial immune responses involve the cellular release of anions and are responsible for the closure of stomatal pores. Detection of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) induces currents mediated via slow-type (S-type) anion channels by a yet not understood mechanism. Here, we show that stomatal closure to fungal chitin is conferred by the major PRRs for chitin recognition, LYK5 and CERK1, the receptor-like cytoplasmic kinase PBL27, and the SLAH3 anion channel. PBL27 has the capacity to phosphorylate SLAH3, of which S127 and S189 are required to activate SLAH3. Full activation of the channel entails CERK1, depending on PBL27. Importantly, both S127 and S189 residues of SLAH3 are required for chitin-induced stomatal closure and anti-fungal immunity at the whole leaf level. Our results demonstrate a short signal transduction module from MAMP recognition to anion channel activation, and independent of ABA-induced SLAH3 activation.

scholarly journals 17β-Estradiol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes

2009 ◽  
Vol 202 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Noriko Tagawa ◽  
Ryosuke Yuda ◽  
Sayaka Kubota ◽  
Midori Wakabayashi ◽  
Yuko Yamaguchi ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Fat Depots ◽  
Mesenteric Fat ◽  
17Β Estradiol ◽  
Transcriptional Pathway ◽  
Insight Into ◽  
Full Activation

17β-Estradiol (E2) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E2 inhibited 11β-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E2 on 11β-HSD1 activity was observed within 5–10 min. Furthermore, acetylation or α-epimerization of 17-hydroxy group of E2 attenuated the inhibitory effect on 11β-HSD1. These results indicate that the inhibition of 11β-HSD1 by E2 depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11β-HSD1, was unaffected by E2. A kinetic study revealed that E2 acted as a non-competitive inhibitor of 11β-HSD1. The inhibitory effect of E2 on 11β-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E2 inhibits 11β-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.

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