scholarly journals Zds1/Zds2–PP2ACdc55 complex specifies signaling output from Rho1 GTPase

2016 ◽  
Vol 212 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Erin M. Jonasson ◽  
Valentina Rossio ◽  
Riko Hatakeyama ◽  
Mitsuhiro Abe ◽  
Yoshikazu Ohya ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Growth ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Specificity ◽  
Actin Organization ◽  
Cell Wall Damage ◽  
Polarized Cell Growth ◽  
Mitogen Activated Protein ◽  
Guanosine Triphosphatase

Budding yeast Rho1 guanosine triphosphatase (GTPase) plays an essential role in polarized cell growth by regulating cell wall glucan synthesis and actin organization. Upon cell wall damage, Rho1 blocks polarized cell growth and repairs the wounds by activating the cell wall integrity (CWI) Pkc1–mitogen-activated protein kinase (MAPK) pathway. A fundamental question is how active Rho1 promotes distinct signaling outputs under different conditions. Here we identified the Zds1/Zds2–protein phosphatase 2ACdc55 (PP2ACdc55) complex as a novel Rho1 effector that regulates Rho1 signaling specificity. Zds1/Zds2–PP2ACdc55 promotes polarized growth and cell wall synthesis by inhibiting Rho1 GTPase-activating protein (GAP) Lrg1 but inhibits CWI pathway by stabilizing another Rho1 GAP, Sac7, suggesting that active Rho1 is biased toward cell growth over stress response. Conversely, upon cell wall damage, Pkc1–Mpk1 activity inhibits cortical PP2ACdc55, ensuring that Rho1 preferentially activates the CWI pathway for cell wall repair. We propose that PP2ACdc55 specifies Rho1 signaling output and that reciprocal antagonism between Rho1–PP2ACdc55 and Rho1–Pkc1 explains how only one signaling pathway is robustly activated at a time.

scholarly journals Cell Wall Stress Depolarizes Cell Growth via Hyperactivation of Rho1

1999 ◽  
Vol 147 (1) ◽  
pp. 163-174 ◽  
Author(s):  
Pierre-Alain Delley ◽  
Michael N. Hall
Keyword(s):  
Cell Wall ◽  
Cell Growth ◽  
Actin Cytoskeleton ◽  
Mammalian Cells ◽  
Wall Stress ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Cell Wall Stress ◽  
Mitogen Activated Protein ◽  
Kinase Cascade

Cells sense and physiologically respond to environmental stress via signaling pathways. Saccharomyces cerevisiae cells respond to cell wall stress by transiently depolarizing the actin cytoskeleton. We report that cell wall stress also induces a transient depolarized distribution of the cell wall biosynthetic enzyme glucan synthase FKS1 and its regulatory subunit RHO1, possibly as a mechanism to repair general cell wall damage. The redistribution of FKS1 is dependent on the actin cytoskeleton. Depolarization of the actin cytoskeleton and FKS1 is mediated by the plasma membrane protein WSC1, the RHO1 GTPase switch, PKC1, and a yet-to-be defined PKC1 effector branch. WSC1 behaves like a signal transducer or a stress-specific actin landmark that both controls and responds to the actin cytoskeleton, similar to the bidirectional signaling between integrin receptors and the actin cytoskeleton in mammalian cells. The PKC1-activated mitogen-activated protein kinase cascade is not required for depolarization, but rather for repolarization of the actin cytoskeleton and FKS1. Thus, activated RHO1 can mediate both polarized and depolarized cell growth via the same effector, PKC1, suggesting that RHO1 may function as a rheostat rather than as a simple on-off switch.

scholarly journals Transcriptional Coregulation by the Cell Integrity Mitogen-Activated Protein Kinase Slt2 and the Cell Cycle Regulator Swi4

2001 ◽  
Vol 21 (19) ◽  
pp. 6515-6528 ◽  
Author(s):  
Kristin Baetz ◽  
Jason Moffat ◽  
Jennifer Haynes ◽  
Michael Chang ◽  
Brenda Andrews
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Wall ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Cell Integrity ◽  
Mitogen Activated Protein

ABSTRACT In Saccharomyces cerevisiae, the heterodimeric transcription factor SBF (for SCB binding factor) is composed of Swi4 and Swi6 and activates gene expression at the G1/S-phase transition of the mitotic cell cycle. Cell cycle commitment is associated not only with major alterations in gene expression but also with highly polarized cell growth; the mitogen-activated protein kinase (MAPK) Slt2 is required to maintain cell wall integrity during periods of polarized growth and cell wall stress. We describe experiments aimed at defining the regulatory pathway involving the cell cycle transcription factor SBF and Slt2-MAPK. Gene expression assays and chromatin immunoprecipitation experiments revealed Slt2-dependent recruitment of SBF to the promoters of the G1 cyclinsPCL1 and PCL2 after activation of the Slt2-MAPK pathway. We performed DNA microarray analysis and identified other genes whose expression was reduced in both SLT2and SWI4 deletion strains. Genes that are sensitive to both Slt2 and Swi4 appear to be uniquely regulated and reveal a role for Swi4, the DNA-binding component of SBF, which is independent of the regulatory subunit Swi6. Some of the Swi4- and Slt2-dependent genes do not require Swi6 for either their expression or for Swi4 localization to their promoters. Consistent with these results, we found a direct interaction between Swi4 and Slt2. Our results establish a new Slt2-dependent mode of Swi4 regulation and suggest roles for Swi4 beyond its prominent role in controlling cell cycle transcription.

scholarly journals Impact of Fungal MAPK Pathway Targets on the Cell Wall

2018 ◽  
Vol 4 (3) ◽  
pp. 93 ◽  
Author(s):  
Jacky Chow ◽  
Marysa Notaro ◽  
Aditi Prabhakar ◽  
Stephen Free ◽  
Paul Cullen
Keyword(s):  
Cell Wall ◽  
Signaling Pathways ◽  
Mapk Pathway ◽  
Normal Growth ◽  
Mitogen Activated Protein Kinase ◽  
Cell Wall Proteins ◽  
Calcofluor White ◽  
Fungal Cell ◽  
Mass Spec ◽  
Mitogen Activated Protein

The fungal cell wall is an extracellular organelle that provides structure and protection to cells. The cell wall also influences the interactions of cells with each other and surfaces. The cell wall can be reorganized in response to changing environmental conditions and different types of stress. Signaling pathways control the remodeling of the cell wall through target proteins that are in many cases not well defined. The Mitogen Activated Protein Kinase pathway that controls filamentous growth in yeast (fMAPK) was required for normal growth in media containing the cell wall perturbing agent Calcofluor White (CFW). A mass spectrometry (MASS-SPEC) approach and analysis of expression profiling data identified cell wall proteins and modifying enzymes whose levels were influenced by the fMAPK pathway. These include Flo11p, Flo10p, Tip1p, Pry2p and the mannosyltransferase, Och1p. Cells lacking Flo11p or Och1p were sensitive to CFW. The identification of cell wall proteins controlled by a MAPK pathway may provide insights into how signaling pathways regulate the cell wall.

scholarly journals Chromatin remodeling by the SWI/SNF complex is essential for transcription mediated by the yeast cell wall integrity MAPK pathway

2012 ◽  
Vol 23 (14) ◽  
pp. 2805-2817 ◽  
Author(s):  
A. Belén Sanz ◽  
Raúl García ◽  
Jose Manuel Rodríguez-Peña ◽  
Sonia Díez-Muñiz ◽  
César Nombela ◽  
...  
Keyword(s):  
Cell Wall ◽  
Chromatin Remodeling ◽  
Mapk Pathway ◽  
Critical Role ◽  
Transcriptional Response ◽  
Wall Stress ◽  
Cell Wall Integrity ◽  
Mitogen Activated Protein Kinase ◽  
Cell Wall Stress ◽  
Mitogen Activated Protein

In Saccharomyces cerevisiae, the transcriptional program triggered by cell wall stress is coordinated by Slt2/Mpk1, the mitogen-activated protein kinase (MAPK) of the cell wall integrity (CWI) pathway, and is mostly mediated by the transcription factor Rlm1. Here we show that the SWI/SNF chromatin-remodeling complex plays a critical role in orchestrating the transcriptional response regulated by Rlm1. swi/snf mutants show drastically reduced expression of cell wall stress–responsive genes and hypersensitivity to cell wall–interfering compounds. On stress, binding of RNA Pol II to the promoters of these genes depends on Rlm1, Slt2, and SWI/SNF. Rlm1 physically interacts with SWI/SNF to direct its association to target promoters. Finally, we observe nucleosome displacement at the CWI-responsive gene MLP1/KDX1, which relies on the SWI/SNF complex. Taken together, our results identify the SWI/SNF complex as a key element of the CWI MAPK pathway that mediates the chromatin remodeling necessary for adequate transcriptional response to cell wall stress.

scholarly journals Role of the Cell Wall Integrity and Filamentous Growth Mitogen-Activated Protein Kinase Pathways in Cell Wall Remodeling during Filamentous Growth

2009 ◽  
Vol 8 (8) ◽  
pp. 1118-1133 ◽  
Author(s):  
Barbara Birkaya ◽  
Abhiram Maddi ◽  
Jyoti Joshi ◽  
Stephen J. Free ◽  
Paul J. Cullen
Keyword(s):  
Cell Wall ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Filamentous Growth ◽  
Cell Wall Integrity ◽  
Mitogen Activated Protein Kinase ◽  
Cell Wall Integrity Pathway ◽  
Cell Wall Remodeling ◽  
Mitogen Activated Protein ◽  
Cell Cell

ABSTRACT Many fungal species including pathogens exhibit filamentous growth (FG) as a means of foraging for nutrients. Genetic screens were performed to identify genes required for FG in the budding yeast Saccharomyces cerevisiae. Genes encoding proteins with established functions in transcriptional activation (MCM1, MATα2, PHD1, MSN2, SIR4, and HMS2), cell wall integrity (MPT5, WSC2, and MID2), and cell polarity (BUD5) were identified as potential regulators of FG. The transcription factors MCM1 and MATα2 induced invasive growth by promoting diploid-specific bipolar budding in haploid cells. Components of the cell wall integrity pathway including the cell surface proteins Slg1p/Wsc1p, Wsc2p, Mid2p, and the mitogen-activated protein kinase (MAPK) Slt2p/Mpk1p contributed to multiple aspects of the FG response including cell elongation, cell-cell adherence, and agar invasion. Mid2p and Wsc2p stimulated the FG MAPK pathway through the signaling mucin Msb2p and components of the MAPK cascade. The FG pathway contributed to cell wall integrity in parallel with the cell wall integrity pathway and in opposition with the high osmolarity glycerol response pathway. Mass spectrometry approaches identified components of the filamentous cell wall including the mucin-like proteins Msb2p, Flo11p, and subtelomeric (silenced) mucin Flo10p. Secretion of Msb2p, which occurs as part of the maturation of the protein, was inhibited by the ß-1,3-glucan layer of the cell wall, which highlights a new regulatory aspect to cell wall remodeling in this organism. Disruption of ß-1,3-glucan linkages induced mucin shedding and resulted in defects in cell-cell adhesion and invasion of cells into the agar matrix.

scholarly journals Candida albicans β-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1

2010 ◽  
Vol 78 (4) ◽  
pp. 1426-1436 ◽  
Author(s):  
Marta Galán-Díez ◽  
David M. Arana ◽  
Diego Serrano-Gómez ◽  
Leonor Kremer ◽  
José M. Casasnovas ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Protein Kinase ◽  
Immune Responses ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Recognition ◽  
Mitogen Activated Protein

ABSTRACT Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.

scholarly journals The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1082
Author(s):  
Amandeep Singh ◽  
Jeehoon Ham ◽  
Joseph William Po ◽  
Navin Niles ◽  
Tara Roberts ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Metastatic Potential ◽  
Pi3k Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Sequencing Data ◽  
Genetic Aberrations ◽  
Progression Model ◽  
Mitogen Activated Protein

Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.

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.

Review of treatment and therapeutic targets in brain arteriovenous malformation

2021 ◽  
pp. 0271678X2110267
Author(s):  
Peipei Pan ◽  
Shantel Weinsheimer ◽  
Daniel Cooke ◽  
Ethan Winkler ◽  
Adib Abla ◽  
...  
Keyword(s):  
Animal Models ◽  
De Novo ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Current Treatment ◽  
Mitogen Activated Protein Kinase ◽  
De Novo Mutations ◽  
Genetic Syndromes ◽  
Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

scholarly journals Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jackson Peterson ◽  
Siqi Li ◽  
Erin Kaltenbrun ◽  
Ozgun Erdogan ◽  
Christopher M. Counter
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Rare Codons ◽  
Synonymous Codons ◽  
Multiple Components ◽  
Human Genes ◽  
Regulatory Module ◽  
Mitogen Activated Protein

AbstractThe ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from rare to common. Transcripts enriched in rare codons are typically associated with poor translation, but in certain settings can be robustly expressed, suggestive of codon-dependent regulation. Given this, we screened a gain-of-function library for human genes that increase the expression of a GFPrare reporter encoded by rare codons. This screen identified multiple components of the mitogen activated protein kinase (MAPK) pathway enhancing GFPrare expression. This effect was reversed with inhibitors of this pathway and confirmed to be both codon-dependent and occur with ectopic transcripts naturally coded with rare codons. Finally, this effect was associated, at least in part, with enhanced translation. We thus identify a potential regulatory module that takes advantage of the redundancy in the genetic code to modulate protein expression.

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