scholarly journals Protein Tyrosine Phosphatase SHP-2 (PTPN11) in Hematopoiesis and Leukemogenesis

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Xia Liu ◽  
Cheng-Kui Qu
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Tyrosine Phosphatase ◽  
Hematologic Malignancies ◽  
Cytokine Signaling ◽  
Interacting Proteins ◽  
Protein Tyrosine ◽  
And Function ◽  
Shed Light

SHP-2 (PTPN11), a ubiquitously expressed protein tyrosine phosphatase, is critical for hematopoietic cell development and function owing to its essential role in growth factor/cytokine signaling. More importantly, germline and somatic mutations in this phosphatase are associated with Noonan syndrome, Leopard syndrome, and childhood hematologic malignancies. The molecular mechanisms by which SHP-2 mutations induce these diseases are not fully understood, as the biochemical bases of SHP-2 functions still remain elusive. Further understanding SHP-2 signaling activities and identification of its interacting proteins/substrates will shed light on the pathogenesis of PTPN11-associated hematologic malignancies, which, in turn, may lead to novel therapeutics for these diseases.

SH2 Domains from Suppressor of Cytokine Signaling-3 and Protein Tyrosine Phosphatase SHP-2 Have Similar Binding Specificities†

Biochemistry ◽  
2002 ◽  
Vol 41 (29) ◽  
pp. 9229-9236 ◽  
Author(s):  
David De Souza ◽  
Louis J. Fabri ◽  
Andrew Nash ◽  
Douglas J. Hilton ◽  
Nicos A. Nicola ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Protein Tyrosine ◽  
Sh2 Domains

scholarly journals Dual Specificity Phosphatases: From Molecular Mechanisms to Biological Function

2019 ◽  
Vol 20 (18) ◽  
pp. 4372 ◽  
Author(s):  
Rafael Pulido ◽  
Roland Lang
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Tyrosine Phosphatase ◽  
Heterogeneous Group ◽  
Class I ◽  
Protein Tyrosine ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...]

scholarly journals The protein tyrosine phosphatase Pez regulates TGFβ, epithelial–mesenchymal transition, and organ development

2007 ◽  
Vol 178 (7) ◽  
pp. 1223-1235 ◽  
Author(s):  
Leila Wyatt ◽  
Carol Wadham ◽  
Lesley A. Crocker ◽  
Michael Lardelli ◽  
Yeesim Khew-Goodall
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Crucial Role ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mdck Cells ◽  
Tyrosine Phosphatase ◽  
Pharyngeal Arches ◽  
Mesenchymal Transition ◽  
Protein Tyrosine ◽  
And Function

Epithelial–mesenchymal transition (EMT), crucial during embryogenesis for new tissue and organ formation, is also considered to be a prerequisite to cancer metastasis. We report here that the protein tyrosine phosphatase Pez is expressed transiently in discrete locations in developing brain, heart, pharyngeal arches, and somites in zebrafish embryos. We also find that Pez knock-down results in defects in these organs, indicating a crucial role in organogenesis. Overexpression of Pez in epithelial MDCK cells causes EMT, with a drastic change in cell morphology and function that is accompanied by changes in gene expression typical of EMT. Transfection of Pez induced TGFβ signaling, critical in developmental EMT with a likely role also in oncogenic EMT. In zebrafish, TGFβ3 is co- expressed with Pez in a number of tissues and its expression was lost from these tissues when Pez expression was knocked down. Together, our data suggest Pez plays a crucial role in organogenesis by inducing TGFβ and EMT.

scholarly journals Regulatory Functions of Protein Tyrosine Phosphatase Receptor Type O in Immune Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Feiling Xie ◽  
Hongmei Dong ◽  
Hao Zhang
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Receptor Type ◽  
Protein Tyrosine ◽  
Cellular Processes

The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.

The Role of Protein Tyrosine Phosphatase, Shp2, in FLT3-ITD-Induced Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1804-1804
Author(s):  
Sarah C Nabinger ◽  
Seiji Fukuda ◽  
Reuben Kapur ◽  
Rebecca Chan
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Erk Activation ◽  
Protein Tyrosine ◽  
Knock Down ◽  
Mammalian Expression ◽  
Tandem Duplications

Abstract Internal tandem duplications of the FMS-like receptor tyrosine kinase (FLT3-ITDs), an in-fame insertion of several amino acids within the juxtamembrane domain, are present in 25% of acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3-ITDs induce FLT3 ligand (FL)-independent hyperactivation of Erk and promiscuous activation of STAT5; however, the molecular mechanisms underlying aberrant activation of these signaling molecules is largely unknown. Tyrosine 599 (Y599) of WT FLT3 recruits the protein tyrosine phosphatase, Shp2, upon stimulation with FL, resulting Erk activation. In several FLT3-ITDs, including N51-FLT3 and N73-FLT3, Y599 is duplicated. These findings led us to hypothesize that increased recruitment of Shp2 to N51-FLT3 or N73- FLT3, via Y599, results in enhanced Shp2 activation and contributes to N51-FLT3- and N73-FLT3-induced cellular hyperproliferation, Erk hyperactivation, and promiscuous STAT5 activation. Using Baf3 cells stably expressing WT FLT3, N51-FLT3, or N73- FLT3, co-immunoprecipitation assays demonstrated that Shp2 is phosphorylated and associates with WT FLT3 in a FL-dependent manner. However, in contrast, Shp2 is constitutively hyperphosphorylated and associated with FLT3-N51 and FLT3-N73 independent of FL stimulation. To investigate the functional role of Shp2 in Flt3-ITD-induced leukemogenesis, Baf3 cells expressing WT FLT3, N51-FLT3, or N73-FLT3 were transfected with a mammalian expression vector encoding a U6 polymerase III– directed Shp2-specific short-hairpin RNA (shRNA) or a scrambled shRNA and selected in puromycin. Western blot analysis revealed significant reduction of Shp2 expression by the Shp2-specific shRNA and no change in Shp2 expression by the scrambled shRNA in all cell lines. Upon knock-down of Shp2 in Baf3/WT-FLT3 cells, proliferation was minimally reduced based on thymidine incorporation assays; however, knock-down of Shp2 in Baf3/N51-FLT3 and Baf3/N73-FLT3 cells significantly reduced proliferation, both at baseline and in response to FL stimulation. Collectively, these data suggest that constitutive recruitment of Shp2 to N51-FLT3 and N73-FLT3 contributes to the FLT3- ITD-induced hyperproliferative phenotype and imply that inhibition of Shp2 function may provide a novel therapeutic approach to FLT3-ITD-bearing leukemias.

scholarly journals Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium

2015 ◽  
Vol 112 (31) ◽  
pp. E4264-E4271 ◽  
Author(s):  
Yoji Murata ◽  
Takenori Kotani ◽  
Yana Supriatna ◽  
Yasuaki Kitamura ◽  
Shinya Imada ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Intestinal Epithelium ◽  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Tyrosine Phosphatase ◽  
Intestinal Immunity ◽  
Protein Tyrosine

Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer–associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10–deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1–deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-κB (NF-κB). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.

scholarly journals Regulation of Early Events in Integrin Signaling by Protein Tyrosine Phosphatase SHP-2

1999 ◽  
Vol 19 (4) ◽  
pp. 3205-3215 ◽  
Author(s):  
Eok-Soo Oh ◽  
Haihua Gu ◽  
Tracy M. Saxton ◽  
John F. Timms ◽  
Sharon Hausdorff ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
In Vivo Studies ◽  
Integrin Signaling ◽  
Cytokine Signaling ◽  
Mapk Activation ◽  
Protein Tyrosine ◽  
Tyrosyl Phosphorylation

ABSTRACT The nontransmembrane protein tyrosine phosphatase SHP-2 plays a critical role in growth factor and cytokine signaling pathways. Previous studies revealed that a fraction of SHP-2 moves to focal contacts upon integrin engagement and that SHP-2 binds to SHP substrate 1 (SHPS-1)/SIRP-1α, a transmembrane glycoprotein with adhesion molecule characteristics (Y. Fujioka et al., Mol. Cell. Biol. 16:6887–6899, 1996; M. Tsuda et al., J. Biol. Chem. 273:13223–13229). Therefore, we asked whether SHP2–SHPS-1 complexes participate in integrin signaling. SHPS-1 tyrosyl phosphorylation increased upon plating of murine fibroblasts onto specific extracellular matrices. Both in vitro and in vivo studies indicate that SHPS-1 tyrosyl phosphorylation is catalyzed by Src family protein tyrosine kinases (PTKs). Overexpression of SHPS-1 in 293 cells potentiated integrin-induced mitogen-activated protein kinase (MAPK) activation, and potentiation required functional SHP-2. To further explore the role of SHP-2 in integrin signaling, we analyzed the responses of SHP-2 exon 3−/− and wild-type cell lines to being plated on fibronectin. Integrin-induced activation of Src family PTKs, tyrosyl phosphorylation of several focal adhesion proteins, MAPK activation, and the ability to spread on fibronectin were defective in SHP-2 mutant fibroblasts but were restored upon SHP-2 expression. Our data suggest a positive-feedback model in which, upon integrin engagement, basal levels of c-Src activity catalyze the tyrosyl phosphorylation of SHPS-1, thereby recruiting SHP-2 to the plasma membrane, where, perhaps by further activating Src PTKs, SHP-2 transduces positive signals for downstream events such as MAPK activation and cell shape changes.

scholarly journals Protein Tyrosine Phosphatase 1B Attenuates Growth Hormone-Mediated JAK2-STAT Signaling

2003 ◽  
Vol 23 (11) ◽  
pp. 3753-3762 ◽  
Author(s):  
Feng Gu ◽  
Nadia Dubé ◽  
Jin Wook Kim ◽  
Alan Cheng ◽  
Maria de Jesus Ibarra-Sanchez ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cytokine Signaling ◽  
Tyrosine Kinase Domain ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ptp 1B

ABSTRACT Protein tyrosine phosphatase-1B (PTP-1B) attenuates insulin, PDGF, EGF, and IGF-I signaling by dephosphorylating tyrosine residues located in the tyrosine kinase domain of the corresponding receptors. More recently, PTP-1B was shown to modulate the action of cytokine signaling via the nonreceptor tyrosine kinase JAK2. Transmission of the growth hormone (GH) signal also depends on JAK2, raising the possibility that PTP-1B modulates GH action. Consistent with this hypothesis, GH increased the abundance of tyrosine-phosphorylated JAK2 associated with a catalytically inactive mutant of PTP-1B. GH-induced JAK2 phosphorylation was greater in knockout (KO) than in wild-type (WT) PTP-1B embryonic fibroblasts and resulted in increased tyrosine phosphorylation of STAT3 and STAT5, while overexpression of PTP-1B reduced the GH-mediated activation of the acid-labile subunit gene. To evaluate the in vivo relevance of these observations, mice were injected with GH under fed and fasted conditions. As expected, tyrosine phosphorylation of JAK2 and STAT5 occurred readily in the livers of fed WT mice and was almost completely abolished during fasting. In contrast, resistance to the action of GH was severely impaired in the livers of fasted KO mice. These results indicate that PTP-1B regulates GH signaling by reducing the extent of JAK2 phosphorylation and suggest that PTP-1B is essential for limiting the action of GH during metabolic stress such as fasting.

scholarly journals Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9504
Author(s):  
Brian V. Hong ◽  
Ji H. Lee ◽  
Robert H. Rice
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Human Keratinocytes ◽  
Oncostatin M ◽  
Epidermal Keratinocytes ◽  
Cytokine Signaling ◽  
Potential Contribution ◽  
Protein Tyrosine ◽  
Phosphatase Inhibitor ◽  
Protein Tyrosine Phosphatase Inhibitor

Cytokine signaling in the epidermis has an important role in maintaining barrier function and is perturbed in pathological conditions. Environmental exposures, such as to metal compounds, are of interest for their potential contribution to skin disease. Present work explores the possibility that vanadate is a more effective protein tyrosine phosphatase inhibitor in human keratinocytes than previously observed in fibroblasts. It focuses on the state of phosphorylation of signal transducer and activator of transcription 1 (STAT1) on tyrosine 701 upon treatment of cultured human keratinocytes with the cytokine oncostatin M, a cutaneous inflammatory mediator that is highly effective in suppressing several differentiation markers and in preserving proliferative potential of keratinocytes. Exposure to sodium vanadate in the medium greatly prolonged the phosphorylation of STAT1, but only at high concentration (>30 µM). Inhibitors of protein tyrosine phosphatases known to dephosphorylate STAT1 (SHP2, TCPTP, PTP1B) were ineffective in mimicking the action of vanadate. The irreversible protein tyrosine phosphatase inhibitor phenyl vinyl sulfonate alone induced STAT1 phosphorylation and appeared to induce its limited cleavage. It also inhibited cross-linked envelope formation, a characteristic step of keratinocyte terminal differentiation, likely due to its reaction with the active site cysteine of keratinocyte transglutaminase. Thus, the key protein tyrosine phosphatase responsible for STAT1 dephosphorylation remains to be identified, and an off-target effect of a potential inhibitor was revealed.

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