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.

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 hVH-5: A Protein Tyrosine Phosphatase Abundant in Brain that Inactivates Mitogen-Activated Protein Kinase

2002 ◽  
Vol 65 (4) ◽  
pp. 1823-1833 ◽  
Author(s):  
Karen J. Martell ◽  
Audrey F. Seasholtz ◽  
Seung P. Kwak ◽  
Kristina K. Clemens ◽  
Jack E. Dixon
Keyword(s):  
Protein Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Mitogen Activated Protein Kinase ◽  
Protein Tyrosine ◽  
Mitogen Activated Protein

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 Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Promotes Inflammation and Accelerates Osteoarthritis by Activating β-Catenin

2021 ◽  
Vol 9 ◽  
Author(s):  
Tenghui Tao ◽  
Danni Luo ◽  
Chenghao Gao ◽  
Hui Liu ◽  
Zehua Lei ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Osteophyte Formation ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Primary Mouse ◽  
Src Homology ◽  
Src Homology 2 Domain

Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation, subchondral bone remodeling and osteophyte formation. Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) has not been fully investigated in the pathogenesis of OA. In this study, we found that SHP2 expression was significantly increased after interleukin-1β (IL-1β) treatment in primary mouse chondrocytes. Inhibition of SHP2 using siRNA reduced MMP3, MMP13 levels, but increased AGGRECAN, COL2A1, SOX9 expression in vitro. On the contrary, overexpression of SHP2 exerted the opposite results and promoted cartilage degradation. Mechanistically, SHP2 activated Wnt/β-catenin signaling possibly through directly binding to β-catenin. SHP2 also induced inflammation through activating Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Our in vivo studies showed that SHP2 knockdown effectively delayed cartilage destruction and reduced osteophyte formation in the mouse model of OA induced by destabilization of the medial meniscus (DMM). Altogether, our study identifies that SHP2 is a novel and potential therapeutic target of OA.

scholarly journals Residue 182 influences the second step of protein-tyrosine phosphatase-mediated catalysis

2004 ◽  
Vol 378 (2) ◽  
pp. 421-433 ◽  
Author(s):  
Anja K. PEDERSEN ◽  
Xiao-Ling GUO ◽  
Karin B. MØLLER ◽  
Günther H. PETERS ◽  
Henrik S. ANDERSEN ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Single Point ◽  
Critical Role ◽  
Enzyme Kinetic ◽  
Protein Tyrosine ◽  
General Base ◽  
Mediated Catalysis ◽  
Formation Step

Previous enzyme kinetic and structural studies have revealed a critical role for Asp181 (PTP1B numbering) in PTP (protein-tyrosine phosphatase)-mediated catalysis. In the E-P (phosphoenzyme) formation step, Asp181 functions as a general acid, while in the E-P hydrolysis step it acts as a general base. Most of our understanding of the role of Asp181 is derived from studies with the Yersinia PTP and the mammalian PTP1B, and to some extent also TC (T-cell)-PTP and the related PTPα and PTP∊. The neighbouring residue 182 is a phenylalanine in these four mammalian enzymes and a glutamine in Yersinia PTP. Surprisingly, little attention has been paid to the fact that this residue is a histidine in most other mammalian PTPs. Using a reciprocal single-point mutational approach with introduction of His182 in PTP1B and Phe182 in PTPH1, we demonstrate here that His182-PTPs, in comparison with Phe182-PTPs, have significantly decreased kcat values, and to a lesser degree, decreased kcat/Km values. Combined enzyme kinetic, X-ray crystallographic and molecular dynamics studies indicate that the effect of His182 is due to interactions with Asp181 and with Gln262. We conclude that residue 182 can modulate the functionality of both Asp181 and Gln262 and therefore affect the E-P hydrolysis step of PTP-mediated catalysis.

scholarly journals The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin-dependent protein kinases in mitosis

2004 ◽  
Vol 380 (3) ◽  
pp. 939-949 ◽  
Author(s):  
Patricia BUKCZYNSKA ◽  
Manuela KLINGLER-HOFFMANN ◽  
Kenneth I. MITCHELHILL ◽  
Mark H. C. LAM ◽  
Melissa CICCOMANCINI ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Cell Protein ◽  
Protein Tyrosine ◽  
Dependent Protein

Two alternatively spliced forms of the human protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) exist: a 48 kDa form that is targeted to the endoplasmic reticulum (TC48) and a shorter 45 kDa form that is targeted to the nucleus (TC45). In this study we have identified Ser-304 (Phe301-Asp-His-Ser304-Pro-Asn-Lys307) as a major TCPTP phosphory-lation site and demonstrate that TC45, but not TC48, is phosphorylated on this site in vivo. Phosphorylation of TC45 on Ser-304 was cell cycle-dependent, and increased as cells progressed from G2 into mitosis, but subsided upon mitotic exit. Ser-304 phosphorylation was increased when cells were arrested in mitosis by microtubule poisons such as nocodazole, but remained unaltered when cells were arrested at the G2/M checkpoint by adriamycin. Phosphorylation of Ser-304 did not alter significantly the phosphatase activity or the protein stability of TC45, and had no apparent effect on TC45 localization. Ser-304 phosphorylation was ablated when cells were treated with the CDK (cyclin-dependent protein kinase) inhibitors roscovitine or SU9516, but remained unaltered when ERK1/2 activation was inhibited with the MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase) inhibitor PD98059. In addition, recombinant CDKs, but not the Polo-like kinase Plk1, phosphorylated Ser-304 in vitro. Our studies identify Ser-304 as a major phosphorylation site in human TCPTP, and the TC45 variant as a novel mitotic CDK substrate.

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