scholarly journals Spatiotemporal control of pathway sensors and cross-pathway feedback regulate a differentiation MAPK pathway in yeast

2021 ◽  
Author(s):  
Aditi Prabhakar ◽  
Beatriz Gonzalez ◽  
Heather Dionne ◽  
Sukanya Basu ◽  
Paul J. Cullen
Keyword(s):  
Cell Differentiation ◽  
Mapk Pathway ◽  
Expression Profiles ◽  
Control Cell ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Interacting Protein ◽  
Bud Neck ◽  
Genes Encoding ◽  
Pathway Regulation

Mitogen-Activated Protein Kinase (MAPK) pathways control cell differentiation and the response to stress. In Saccharomyces cerevisiae, the MAPK pathway that controls filamentous growth (fMAPK) shares components with the pathway that regulates the response to osmotic stress (HOG). Here, we show that the two pathways exhibit different patterns of activity throughout the cell cycle. The different patterns resulted from different expression profiles of genes encoding mucin sensors that regulate the pathways. Cross-pathway regulation from the fMAPK pathway stimulated the HOG pathway, presumably to modulate fMAPK pathway activity. We also show that the shared tetraspan protein, Sho1p, which has a dynamic localization pattern, induced the fMAPK pathway at the mother-bud neck. A Sho1p-interacting protein, Hof1p, which also localizes to the mother-bud neck and regulates cytokinesis, also regulated the fMAPK pathway. Therefore, spatial and temporal regulation of pathway sensors, and cross-pathway regulation, control a MAPK pathway that regulates cell differentiation in yeast.

scholarly journals Spatiotemporal Control of Pathway Sensors and Cross-Pathway Feedback Regulate a Cell Differentiation MAPK Pathway in Yeast

2020 ◽  
Author(s):  
Aditi Prabhakar ◽  
Beatriz Gonzalez ◽  
Heather Dionne ◽  
Sukanya Basu ◽  
Paul J. Cullen
Keyword(s):  
Cell Differentiation ◽  
Mapk Pathway ◽  
Expression Profiles ◽  
Control Cell ◽  
Mapk Signaling ◽  
Hog Pathway ◽  
Temporal Regulation ◽  
Mapk Pathways ◽  
Bud Neck ◽  
A Cell

ABSTRACTMitogen-Activated Protein Kinase (MAPK) pathways control cell differentiation and the response to stress. MAPK pathways can share components with other pathways yet induce specific responses through mechanisms that remain unclear. In Saccharomyces cerevisiae, the MAPK pathway that controls filamentous growth (fMAPK) shares components with the MAPK pathway that regulates the response to osmotic stress (HOG). By exploring temporal regulation of MAPK signaling, we show here that the two pathways exhibited different patterns of activity throughout the cell cycle. The different patterns resulted from different expression profiles of genes encoding the mucin sensors (MSB2 for fMAPK and HKR1 for HOG). We also show that positive feedback through the fMAPK pathway stimulated the HOG pathway, presumably to modulate fMAPK pathway activity. By exploring spatial regulation of MAPK signaling, we found that the shared tetraspan protein, Sho1p, which has a dynamic localization pattern, induced the fMAPK pathway at the mother-bud neck. A Sho1p-interacting protein, Hof1p, which also localizes to the mother-bud neck and regulates cytokinesis, also regulated the fMAPK pathway. Therefore, spatial and temporal regulation of pathway sensors, and cross-pathway feedback, regulate a MAPK pathway that controls a cell differentiation response in yeast.

scholarly journals A Rab Escort Protein Regulates the MAPK Pathway That Controls Filamentous Growth in Yeast

2020 ◽  
Author(s):  
Sheida Jamalzadeh ◽  
Paul J. Cullen
Keyword(s):  
Mapk Pathway ◽  
Filamentous Growth ◽  
Mapk Signaling ◽  
Hog Pathway ◽  
Mapk Pathways ◽  
A Genome ◽  
Dependent Signal ◽  
Nutrient Signaling ◽  
Pathway Regulation ◽  
Yeast Genes

ABSTRACTMAPK pathways regulate different responses yet can share a subset of common components. In this study, a genome-wide screen was performed to identify genes that, when overexpressed, induce a growth reporter (FUS1-HIS3) that responds to ERK-type MAPK pathways (Mating/filamentous growth or fMAPK) but not p38-type MAPK pathways (HOG) in yeast. Approximately 4,500 plasmids overexpressing individual yeast genes were introduced into strains containing the FUS1-HIS3 reporter by high-throughput transformation. Candidate genes were identified by measuring the degree of growth, which was a reflection of reporter activity. Of fourteen genes identified and validated by re-testing, two were metabolic controls (HIS3 and ATR1), five had established roles in regulating ERK-type pathways (STE4, STE7, BMH1, BMH2, MIG2) and seven represent potentially new regulators of MAPK signaling (RRN6, CIN5, MRS6, KAR2, TFA1, RSC3, RGT2). MRS6 encodes a Rab escort protein and effector of the TOR pathway that plays an established role in nutrient signaling. MRS6 overexpression stimulated filamentous/invasive growth and phosphorylation of the ERK-type fMAPK, Kss1. Overexpression of MRS6 reduced the osmotolerance of cells and phosphorylation of the p38/HOG pathway MAPK, Hog1. Mrs6 interacted with the PAK kinase Ste20 and MAPKK Ste7 by two-hybrid analysis. Collectively, the data indicate that Mrs6 may function to selectively propagate an ERK-dependent signal. Generally speaking, the identification of new MAPK pathway regulators by genetic screening in yeast may be a useful resource for understanding signaling pathway regulation.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals PaTrx1 and PaTrx3, Two Cytosolic Thioredoxins of the Filamentous Ascomycete Podospora anserina Involved in Sexual Development and Cell Degeneration

2007 ◽  
Vol 6 (12) ◽  
pp. 2323-2331 ◽  
Author(s):  
Fabienne Malagnac ◽  
Benjamin Klapholz ◽  
Philippe Silar
Keyword(s):  
Disulfide Bonds ◽  
Mapk Pathway ◽  
Sulfur Metabolism ◽  
Podospora Anserina ◽  
Mitogen Activated Protein Kinase ◽  
Cell Degeneration ◽  
Stress Genes ◽  
Filamentous Ascomycete ◽  
Genes Encoding ◽  
Protein Disulfide Bonds

ABSTRACT In various organisms, thioredoxins are known to be involved in the reduction of protein disulfide bonds and in protecting the cell from oxidative stress. Genes encoding thioredoxins were found by searching the complete genome sequence of the filamentous ascomycete Podospora anserina. Among them, PaTrx1, PaTrx2, and PaTrx3 are predicted to be canonical cytosolic proteins without additional domains. Targeted disruption of PaTrx1, PaTrx2, and PaTrx3 shows that PaTrx1 is the major thioredoxin involved in sulfur metabolism. Deletions have no effect on peroxide resistance; however, data show that either PaTrx1 or PaTrx3 is necessary for sexual reproduction and for the development of the crippled growth cell degeneration (CG), processes that also required the PaMpk1 mitogen-activated protein kinase (MAPK) pathway. Since PaTrx1 PaTrx3 mutants show not an enhancement but rather an impairment in CG, it seems unlikely that PaTrx1 and PaTrx3 thioredoxins participate in the inhibition of this MAPK pathway. Altogether, these results underscore a role for thioredoxins in fungal development.

scholarly journals A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38α/β MAPK activity and myogenic differentiation

2008 ◽  
Vol 182 (3) ◽  
pp. 497-507 ◽  
Author(s):  
Jong-Sun Kang ◽  
Gyu-Un Bae ◽  
Min-Jeong Yi ◽  
Youn-Joo Yang ◽  
Ji-Eun Oh ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Surface ◽  
Mapk Pathway ◽  
Myogenic Differentiation ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Myoblast Differentiation ◽  
Loss Of Function ◽  
Surface Receptor

The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38α/β pathway scaffold protein JLP and, via JLP, p38α/β itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo–Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38α/β activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38α/β activation during cell differentiation.

scholarly journals Cdc42p-Interacting Protein Bem4p Regulates the Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

2014 ◽  
Vol 35 (2) ◽  
pp. 417-436 ◽  
Author(s):  
Andrew Pitoniak ◽  
Colin A. Chavel ◽  
Jacky Chow ◽  
Jeremy Smith ◽  
Diawoye Camara ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Filamentous Growth ◽  
Cell Polarization ◽  
Mitogen Activated Protein Kinase ◽  
Specific Response ◽  
Ph Domain ◽  
Interacting Protein ◽  
Mitogen Activated Protein ◽  
Growth Pathway

The ubiquitous Rho (Ras homology) GTPase Cdc42p can function in different settings to regulate cell polarity and cellular signaling. How Cdc42p and other proteins are directed to function in a particular context remains unclear. We show that the Cdc42p-interacting protein Bem4p regulates the mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth inSaccharomyces cerevisiae. Bem4p controlled the filamentous-growth pathway but not other MAPK pathways (mating or high-osmolarity glycerol response [HOG]) that also require Cdc42p and other shared components. Bem4p associated with the plasma membrane (PM) protein, Sho1p, to regulate MAPK activity and cell polarization under nutrient-limiting conditions that favor filamentous growth. Bem4p also interacted with the major activator of Cdc42p, the guanine nucleotide exchange factor (GEF) Cdc24p, which we show also regulates the filamentous-growth pathway. Bem4p interacted with the pleckstrin homology (PH) domain of Cdc24p, which functions in an autoinhibitory capacity, and was required, along with other pathway regulators, to maintain Cdc24p at polarized sites during filamentous growth. Bem4p also interacted with the MAPK kinase kinase (MAPKKK) Ste11p. Thus, Bem4p is a new regulator of the filamentous-growth MAPK pathway and binds to general proteins, like Cdc42p and Ste11p, to promote a pathway-specific response.

scholarly journals Unique and Redundant Roles for HOG MAPK Pathway Components as Revealed by Whole-Genome Expression Analysis

2004 ◽  
Vol 15 (2) ◽  
pp. 532-542 ◽  
Author(s):  
Sean M. O'Rourke ◽  
Ira Herskowitz
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Whole Genome ◽  
Hog Pathway ◽  
General Stress Response ◽  
High Osmolarity ◽  
Genome Expression ◽  
Mitogen Activated Protein ◽  
Whole Genome Expression

The Saccharomyces cerevisiae high osmolarity glycerol (HOG) mitogen-activated protein kinase pathway is required for osmoadaptation and contains two branches that activate a mitogen-activated protein kinase (Hog1) via a mitogen-activated protein kinase kinase (Pbs2). We have characterized the roles of common pathway components (Hog1 and Pbs2) and components in the two upstream branches (Ste11, Sho1, and Ssk1) in response to elevated osmolarity by using whole-genome expression profiling. Several new features of the HOG pathway were revealed. First, Hog1 functions during gene induction and repression, cross talk inhibition, and in governing the regulatory period. Second, the phenotypes of pbs2 and hog1 mutants are identical, indicating that the sole role of Pbs2 is to activate Hog1. Third, the existence of genes whose induction is dependent on Hog1 and Pbs2 but not on Ste11 and Ssk1 suggests that there are additional inputs into Pbs2 under our inducing conditions. Fourth, the two upstream pathway branches are not redundant: the Sln1-Ssk1 branch has a much more prominent role than the Sho1-Ste11 branch for activation of Pbs2 by modest osmolarity. Finally, the general stress response pathway and both branches of the HOG pathway all function at high osmolarity. These studies demonstrate that cells respond to increased osmolarity by using different signal transduction machinery under different conditions.

Similar Aquaporin9 and MAPK Expression Profiles in the Liver of Types 1 and 2 Diabetes Mellitus

2018 ◽  
Vol 50 (05) ◽  
pp. 414-421 ◽  
Author(s):  
Jiaojiao Hou ◽  
Yuan Li ◽  
Xüxia Ren ◽  
Fei Gao ◽  
Yuqin Chen ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Mapk Pathway ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Mitogen Activated Protein Kinase ◽  
Control Group ◽  
Limited Information ◽  
Mitogen Activated Protein ◽  
Water Glycerol ◽  
Glycerol Uptake

AbstractAquaporin-9 (AQP9) is an aquaglyceroporin that biophysically conducts water, glycerol, and other small solutes. AQP9 is expressed in hepatocytes on the sinusoidal surfaces of hepatocyte plates in the liver, where it is considered responsible for the glycerol uptake in gluconeogenesis. However, limited information is available on the expression and regulating mechanism of AQP9 in different hyperglycemia models. Thus, this study examined the expression patterns of AQP9 and mitogen-activated protein kinase (MAPK) in Types 1 and 2 diabetes mellitus (DM) to clarify the roles and regulating mechanism of AQP9 in gluconeogenesis. Compared with the control group, the AQP9 expression significantly increased in both Types 1 and 2 DM, and the increased expression was associated with the activation of phosphorylated JNK (p-JNK) and the inhibition of phosphorylated p38 (p-p38). By contrast, phosphorylated ERK remained stable in the liver with Type 1 or 2 DM. These effects could be reversed by insulin treatment. That is, insulin downregulated AQP9 by inhibiting p-JNK and activating p-p38. The upregulation of AQP9 could be involved in gluconeogenesis and co-regulated by the JNK and p38 MAPK pathway in both Types 1 and 2 DM.

RASopathies in multidisciplinary pediatric hospita

2020 ◽  
pp. 21-23
Author(s):  
Н.В. Журкова ◽  
Л.А. Гандаева ◽  
А.А. Пушков ◽  
Е.Н. Басаргина ◽  
А.В. Пахомов ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Inherited Diseases ◽  
Cardiofaciocutaneous Syndrome ◽  
Genes Encoding ◽  
Mitogen Activated Protein ◽  
Anagen Hair

RAS-патии - группа наследственных заболеваний, возникающая вследствие нарушения регуляции функции RAS/MAPK внутриклеточных путей (Ras/mitogen-activated protein kinase). Суммарная частота заболеваний данной группы - 1 случай на 1000 новорожденных. Наиболее часто среди RAS-патий встречается синдром Нунан. В настоящее время описано 13 генов, мутации которых отвечают за развитие данного заболевания, включая ген SHOC2, ассоциированный с Нунан-подобным синдромом и измененной структурой волос (Noonan-like syndrome with loose anagen hair) и ген LZTR1, мутации в котором приводят к развитию синдрома Нунан, тип 2 с аутосомно-рецессивным типом наследования. RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

scholarly journals Ptc1, a Type 2C Ser/Thr Phosphatase, Inactivates the HOG Pathway by Dephosphorylating the Mitogen-Activated Protein Kinase Hog1

2001 ◽  
Vol 21 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Janel Warmka ◽  
Jennifer Hanneman ◽  
Ji Lee ◽  
Dipesh Amin ◽  
Irene Ota
Keyword(s):  
Protein Kinase ◽  
Osmotic Stress ◽  
Metal Ion ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Mitogen Activated Protein

ABSTRACT The HOG (high-osmolarity glycerol) mitogen-activated protein kinase (MAPK) pathway regulates the osmotic stress response in the yeast Saccharomyces cerevisiae. Three type 2C Ser/Thr phosphatases (PTCs), Ptc1, Ptc2, and Ptc3, have been isolated as negative regulators of this pathway. Previously, multicopy expression of PTC1 and PTC3 was shown to suppress lethality of the sln1Δ strain due to hyperactivation of the HOG pathway. In this work, we show thatPTC2 also suppresses sln1Δ lethality. Furthermore, the phosphatase activity of these PTCs was needed for suppression, as mutation of a conserved Asp residue, likely to coordinate a metal ion, inactivated PTCs. Further analysis of Ptc1 function in vivo showed that it inactivates the MAPK, Hog1, but not the MEK, Pbs2. In the wild type, Hog1 kinase activity increased transiently, ∼12-fold in response to osmotic stress, while overexpression of PTC1 limited activation to ∼3-fold. In contrast, overexpression of PTC1 did not inhibit phosphorylation of Hog1 Tyr in the phosphorylation lip, suggesting that Ptc1 does not act on Pbs2. Deletion of PTC1 also strongly affected Hog1, leading to high basal Hog1 activity and sustained Hog1 activity in response to osmotic stress, the latter being consistent with a role for Ptc1 in adaptation. In vitro, Ptc1 but not the metal binding site mutant, Ptc1D58N, inactivated Hog1 by dephosphorylating the phosphothreonine but not the phosphotyrosine residue in the phosphorylation lip. Consistent with its role as a negative regulator of Hog1, which accumulates in the nucleus upon activation, Ptc1 was found in both the nucleus and the cytoplasm. Thus, one function of Ptc1 is to inactivate Hog1.

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