scholarly journals Distinct and Redundant Roles of Protein Tyrosine Phosphatases Ptp1 and Ptp2 in Governing the Differentiation and Pathogenicity of Cryptococcus neoformans

2014 ◽  
Vol 13 (6) ◽  
pp. 796-812 ◽  
Author(s):  
Kyung-Tae Lee ◽  
Hyo-Jeong Byun ◽  
Kwang-Woo Jung ◽  
Joohyeon Hong ◽  
Eunji Cheong ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Negative Feedback ◽  
Stress Responses ◽  
Protein Tyrosine Phosphatases ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Tyrosine Phosphatases ◽  
Hog Pathway ◽  
Content Type ◽  
Protein Tyrosine

ABSTRACTProtein tyrosine phosphatases (PTPs) serve as key negative-feedback regulators of mitogen-activated protein kinase (MAPK) signaling cascades. However, their roles and regulatory mechanisms in human fungal pathogens remain elusive. In this study, we characterized the functions of two PTPs, Ptp1 and Ptp2, inCryptococcus neoformans, which causes fatal meningoencephalitis.PTP1andPTP2were found to be stress-inducible genes, which were controlled by the MAPK Hog1 and the transcription factor Atf1. Ptp2 suppressed the hyperphosphorylation of Hog1 and was involved in mediating vegetative growth, sexual differentiation, stress responses, antifungal drug resistance, and virulence factor regulation through the negative-feedback loop of the HOG pathway. In contrast, Ptp1 was not essential for Hog1 regulation, despite its Hog1-dependent induction. However, in the absence of Ptp2, Ptp1 served as a complementary PTP to control some stress responses. In differentiation, Ptp1 acted as a negative regulator, but in a Hog1- and Cpk1-independent manner. Additionally, Ptp1 and Ptp2 localized to the cytosol but were enriched in the nucleus during the stress response, affecting the transient nuclear localization of Hog1. Finally, Ptp1 and Ptp2 played minor and major roles, respectively, in the virulence ofC. neoformans. Taken together, our data suggested that PTPs could be exploited as novel antifungal targets.

scholarly journals Differential Regulation of the Cell Wall Integrity Mitogen-Activated Protein Kinase Pathway in Budding Yeast by the Protein Tyrosine Phosphatases Ptp2 and Ptp3

1999 ◽  
Vol 19 (11) ◽  
pp. 7651-7660 ◽  
Author(s):  
Christopher P. Mattison ◽  
Scott S. Spencer ◽  
Kurt A. Kresge ◽  
Ji Lee ◽  
Irene M. Ota
Keyword(s):  
Cell Wall ◽  
Protein Tyrosine Phosphatases ◽  
Negative Regulator ◽  
Cell Wall Integrity ◽  
Dependent Manner ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Growth Defects ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity and protein tyrosine phosphatases (PTPs) in yeasts. InSaccharomyces cerevisiae, two PTPs, Ptp2 and Ptp3, inactivate the MAPKs, Hog1 and Fus3, with different specificities. To further examine the functions and substrate specificities of Ptp2 and Ptp3, we tested whether they could inactivate a third MAPK, Mpk1, in the cell wall integrity pathway. In vivo and in vitro evidence indicates that both PTPs inactivate Mpk1, but Ptp2 is the more effective negative regulator. Multicopy expression of PTP2, but not PTP3, suppressed growth defects due to the MEK kinase mutation, BCK1-20, and the MEK mutation,MKK1-386, that hyperactivate this pathway. In addition, deletion of PTP2, but not PTP3, exacerbated growth defects due to MKK1-386. Other evidence supported a role for Ptp3 in this pathway. Expression of MKK1-386 was lethal in the ptp2Δ ptp3Δ strain but not in either single PTP deletion strain. In addition, the ptp2Δ ptp3Δ strain showed higher levels of heat stress-induced Mpk1-phosphotyrosine than the wild-type strain or strains lacking either PTP. The PTPs also showed differences in vitro. Ptp2 was more efficient than Ptp3 at binding and dephosphorylating Mpk1. Another factor that may contribute to the greater effectiveness of Ptp2 is its subcellular localization. Ptp2 is predominantly nuclear whereas Ptp3 is cytoplasmic, suggesting that active Mpk1 is present in the nucleus. Last, PTP2 but not PTP3 transcript increased in response to heat shock in a Mpk1-dependent manner, suggesting that Ptp2 acts in a negative feedback loop to inactivate Mpk1.

scholarly journals Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells

2017 ◽  
Vol 59 (4) ◽  
pp. 325-337 ◽  
Author(s):  
William J Stanley ◽  
Prerak M Trivedi ◽  
Andrew P Sutherland ◽  
Helen E Thomas ◽  
Esteban N Gurzov
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Protein Tyrosine Phosphatases ◽  
Negative Regulator ◽  
Tyrosine Phosphatases ◽  
Β Cells ◽  
Β Cell ◽  
Protein Tyrosine ◽  
Tnf Α ◽  
Ifn Γ

Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β are released in the islet during the autoimmune assault and signal in β-cells through phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate phosphorylative signalling and are associated with the development of T1D. Here, we observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese diabetic (NOD) mice. To clarify the role of these PTPs in β-cells/islets, we took advantage of CRISPR/Cas9 technology and pharmacological approaches to inactivate both proteins. We identify PTPN6 as a negative regulator of TNF-α-induced β-cell death, through JNK-dependent BCL-2 protein degradation. In contrast, PTPN1 acts as a positive regulator of IFN-γ-induced STAT1-dependent gene expression, which enhanced autoimmune destruction of β-cells. Importantly, PTPN1 inactivation by pharmacological modulation protects β-cells and primary mouse islets from cytokine-mediated cell death. Thus, our data point to a non-redundant effect of PTP regulation of cytokine signalling in β-cells in autoimmune diabetes.

scholarly journals Tyrosine Phosphorylation and Dephosphorylation in Burkholderia cenocepacia Affect Biofilm Formation, Growth under Nutritional Deprivation, and Pathogenicity

2015 ◽  
Vol 82 (3) ◽  
pp. 843-856 ◽  
Author(s):  
Angel Andrade ◽  
Faviola Tavares-Carreón ◽  
Maryam Khodai-Kalaki ◽  
Miguel A. Valvano
Keyword(s):  
Molecular Weight ◽  
Protein Tyrosine Phosphatases ◽  
Burkholderia Cenocepacia ◽  
Low Molecular Weight ◽  
Molecular Weight Protein ◽  
Tyrosine Phosphatases ◽  
Content Type ◽  
Protein Tyrosine ◽  
Weight Protein ◽  
Low Molecular Weight Protein

ABSTRACTBurkholderia cenocepacia, a member of theB. cepaciacomplex (Bcc), is an opportunistic pathogen causing serious chronic infections in patients with cystic fibrosis. Tyrosine phosphorylation has emerged as an important posttranslational modification modulating the physiology and pathogenicity of Bcc bacteria. Here, we investigated the predicted bacterial tyrosine kinases BCAM1331 and BceF and the low-molecular-weight protein tyrosine phosphatases BCAM0208, BceD, and BCAL2200 ofB. cenocepaciaK56-2. We show that BCAM1331, BceF, BCAM0208, and BceD contribute to biofilm formation, while BCAL2200 is required for growth under nutrient-limited conditions. Multiple deletions of either tyrosine kinase or low-molecular-weight protein tyrosine phosphatase genes resulted in the attenuation ofB. cenocepaciaintramacrophage survival and reduced pathogenicity in theGalleria mellonellalarval infection model. Experimental evidence indicates that BCAM1331 displays reduced tyrosine autophosphorylation activity compared to that of BceF. With the artificial substratep-nitrophenyl phosphate, the phosphatase activities of the three low-molecular-weight protein tyrosine phosphatases demonstrated similar kinetic parameters. However, only BCAM0208 and BceD could dephosphorylate BceF. Further, BCAL2200 became tyrosine phosphorylatedin vivoand catalyzed its autodephosphorylation. Together, our data suggest that despite having similar biochemical activities, low-molecular-weight protein tyrosine phosphatases and tyrosine kinases have both overlapping and specific roles in the physiology ofB. cenocepacia.

Sign in / Sign up

Export Citation Format

Share Document