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 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.

scholarly journals Identification of Major Binding Proteins and Substrates for the SH2-Containing Protein Tyrosine Phosphatase SHP-1 in Macrophages

1998 ◽  
Vol 18 (7) ◽  
pp. 3838-3850 ◽  
Author(s):  
John F. Timms ◽  
Kristen Carlberg ◽  
Haihua Gu ◽  
Haiyan Chen ◽  
Shubhangi Kamatkar ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Kinase Activity ◽  
Tyrosine Phosphatase ◽  
Regulatory Protein ◽  
Protein Tyrosine ◽  
Sh2 Domains ◽  
Receptor Complexes ◽  
Multiple Signaling ◽  
Tyrosyl Phosphorylation ◽  
Stimulating Factor

ABSTRACT The protein tyrosine phosphatase SHP-1 is a critical regulator of macrophage biology, but its detailed mechanism of action remains largely undefined. SHP-1 associates with a 130-kDa tyrosyl-phosphorylated species (P130) in macrophages, suggesting that P130 might be an SHP-1 regulator and/or substrate. Here we show that P130 consists of two transmembrane glycoproteins, which we identify as PIR-B/p91A and the signal-regulatory protein (SIRP) family member BIT. These proteins also form separate complexes with SHP-2. BIT, but not PIR-B, is in a complex with the colony-stimulating factor 1 receptor (CSF-1R), suggesting that BIT may direct SHP-1 to the CSF-1R. BIT and PIR-B bind preferentially to substrate-trapping mutants of SHP-1 and are hyperphosphorylated in macrophages from motheaten viable mice, which express catalytically impaired forms of SHP-1, indicating that these proteins are SHP-1 substrates. However, BIT and PIR-B are hypophosphorylated in motheaten macrophages, which completely lack SHP-1 expression. These data suggest a model in which SHP-1 dephosphorylates specific sites on BIT and PIR-B while protecting other sites from dephosphorylation via its SH2 domains. Finally, BIT and PIR-B associate with two tyrosyl phosphoproteins and a tyrosine kinase activity. Tyrosyl phosphorylation of these proteins and the level of the associated kinase activity are increased in the absence of SHP-1. Our data suggest that BIT and PIR-B recruit multiple signaling molecules to receptor complexes, where they are regulated by SHP-1 and/or SHP-2.

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.

Inhibition of the activity of protein tyrosine phosphatase 1C by its SH2 domains

Biochemistry ◽  
1993 ◽  
Vol 32 (49) ◽  
pp. 13414-13418 ◽  
Author(s):  
Richard Townley ◽  
Shi Hsiang Shen ◽  
Denis Banville ◽  
Chidambaram Ramachandran
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Sh2 Domains

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.

Sign in / Sign up

Export Citation Format

Share Document