SH2-Containing Protein Tyrosine Phosphatase-1 (SHP-1) Association with Jak2 in UT-7/Epo Cells

Wu, Ding Wen; Stark, Kenneth; Dunnington, Damien J.; Dillon, Susan B.; Yi, Taolin; Jones, Christopher C.; Pelus, Louis M.

doi:10.1006/bcmd.2000.0273

Cited by 12 publications

(15 citation statements)

References 28 publications

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“…We and others showed previously that SHP-1 dephosphorylates the Jak family kinases to down-regulate signaling initiated by cytokines (12,16,18,(35)(36)(37). Among the Jak kinases, IL-3 specifically activates the Jak2 kinase that phosphorylates the Stat5 protein to regulate gene expression (39).…”

Section: Discussionmentioning

confidence: 99%

“…A functional role of SHP-1 in dephosphorylating the Jak family kinases during cytokine signaling has been documented (16,18,(35)(36)(37). To determine whether sodium stibogluconate inhibits SHP-1 in vivo, we examined the effect of the drug on IL-3-induced Jak2 tyrosine phosphorylation in Baf3 cells (Fig.…”

Section: Sodium Stibogluconate Induces Tyrosine Phosphorylation Of Cementioning

confidence: 99%

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Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Pathak

2001

The Journal of Immunology

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178

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Using in vitro protein tyrosine phosphatase (PTPase) assays, we found that sodium stibogluconate, a drug used in treatment of leishmaniasis, is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2, and PTP1B but not the dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1. Sodium stibogluconate inhibited 99% of SHP-1 activity at 10 μg/ml, a therapeutic concentration of the drug for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B required 100 μg/ml sodium stibogluconate, demonstrating differential sensitivities of PTPases to the inhibitor. The drug appeared to target the SHP-1 domain because it showed similar in vitro inhibition of SHP-1 and a mutant protein containing the SHP-1 PTPase domain alone. Moreover, it forms a stable complex with the PTPase: in vitro inhibition of SHP-1 by the drug was not removed by a washing process effective in relieving the inhibition of SHP-1 by the reversible inhibitor suramin. The inhibition of cellular PTPases by the drug was suggested by its rapid induction of tyrosine phosphorylation of cellular proteins in Baf3 cells and its augmentation of IL-3-induced Janus family kinase 2/Stat5 tyrosine phosphorylation and proliferation of Baf3 cells. The augmentation of the opposite effects of GM-CSF and IFN-α on TF-1 cell growth by the drug indicated its broad activities in the signaling of various cytokines. These data represent the first evidence that sodium stibogluconate inhibits PTPases and augments cytokine responses. Our results provide novel insights into the pharmacological effects of the drug and suggest potential new therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Section: Sodium Stibogluconate Induces Tyrosine Phosphorylation Of Cementioning

confidence: 99%

Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Pathak

2001

The Journal of Immunology

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178

168

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“…[39][40][41] SHP1 has also been shown to downregulate Src-family kinases such as Lck, Fyn, 42 and ZAP-70. 43,44 SHP1 also plays an important role in the negative regulation of the signaling pathway involving the JAK family kinases 19,45 and STATs. 46 As these pathways are activated by NPM-ALK, it is possible that SHP1 also acts on several other signaling molecules downstream from the NPM-ALK oncogenic protein.…”

Section: Discussionmentioning

confidence: 99%

SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling

Honorat

Ragab

Lamant

et al. 2006

Blood

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Anaplastic large-cell lymphoma (ALCL) is frequently associated with the 2;5 translocation and expresses the NPM-ALK fusion protein, which possesses a constitutive tyrosine kinase activity. We analyzed SHP1 tyrosine phosphatase expression and activity in 3 ALK-positive ALCL cell lines (Karpas 299, Cost, and SU-DHL1) and in lymph node biopsies (n ‫؍‬ 40). We found an inverse correlation between the level of NPM-ALK phosphorylation and SHP1 phosphatase activity. Pull-down and coimmunoprecipitation experiments demonstrated a SHP1/NPM-ALK association. Furthermore, confocal microscopy performed on ALCL cell lines and biopsy specimens showed the colocalization of the 2 proteins in cytoplasmic bodies containing Y664-phosphorylated NPM-ALK. Dephosphorylation of NPM-ALK by SHP1 demonstrated that NPM-ALK was a SHP1 substrate. IntroductionALK-positive anaplastic large-cell lymphomas (ALCLs) are characterized by the expression of a hybrid protein, associating the cytoplasmic portion of the ALK tyrosine kinase (anaplastic lymphoma kinase) with a partner protein. This hybrid kinase is often encoded by the NPM-ALK fusion gene resulting from the (2;5)(p23; q35) chromosomal translocation. However, several reports have shown that the ALK gene at 2p23 may also be involved in a number of variant translocations. 1,2 The dimerization of NPM-ALK through NPM mimics ligand binding and leads to the constitutive activation of the ALK tyrosine kinase through tyrosine transphosphorylation and autophosphorylation. 3,4 Phosphorylated NPM-ALK promotes cell survival and tumorigenesis through the activation of multiple SH2-domain-containing proteins, including the phospholipase C ␥1 (PLC␥1), PI-3Kinase/AKT, and the JAK/STAT pathways, that control cell-cycle progression. [5][6][7][8][9][10][11] It is likely that the oncogenic potential of NPM-ALK may be related with its kinase capability and consequently its tyrosine phosphorylation level. 1,12 As previously reported, pp60c-src of the Src-family kinases interacts with NPM-ALK, participates in its phosphorylation, and could be an important actor in NPM-ALK-mediated mitogenicity. 13 Although the mechanism of NPM-ALK activation is well documented, the downregulation process is totally unknown.Phosphorylation of proteins on tyrosine residues is regulated by the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Deregulation of the balance that exists between these 2 groups of enzymes can trigger the accumulation of tyrosine-phosphorylated proteins, which, in turn, can lead to abnormal cell proliferation and tumorigenesis. Two SH2-domaincontaining phosphotyrosine phosphatases, SHP1 and SHP2, are widely implicated in the regulation of signaling pathways involved in cell proliferation, differentiation, and survival. 14 It is well established that these 2 PTPs are involved in the pathogenesis of lymphoma, leukemia, and other types of cancers. 15,16 Despite their high degree of homology, SHP1 and SHP2 have completely distinct expression profiles and functions. In contr...

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“…For example, the protein tyrosine-specific phosphatase SHP-1 binds to the pY344 motif as well as to the JAK2 kinase. 23,24 Other possible inhibitory molecules such as cytokine-inducible SH2-containing protein (CIS) and suppressor of cytokine signaling-2 (SOCS2) are known to associate with pY344 and pY402. 25 The interaction of SH2 domain-containing inositol-phosphatase (SHIP) with the EpoR was also demonstrated, but it is not clear whether the association is direct or via the Gab-1 or Shc adaptors.…”

Section: Introductionmentioning

confidence: 99%

“…For example, the protein tyrosine-specific phosphatase SHP-1 binds to the pY344 motif as well as to the JAK2 kinase. 23,24 Other possible inhibitory molecules such as cytokine-inducible SH2-containing protein (CIS) and suppressor of cytokine signaling-2 (SOCS2) are known to associate with pY344 and For personal use only. on May 9, 2018. by guest www.bloodjournal.org From pY402.…”

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confidence: 99%

A systematic scan of interactions with tyrosine motifs in the erythropoietin receptor using a mammalian 2-hybrid approach

Montoye

Lemmens

Catteeuw

et al. 2005

Blood

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Signaling via the erythropoietin receptor (EpoR) depends on the interaction of several proteins with phosphorylated tyrosine-containing motifs in its cytosolic domain. Detailed mapping of these interactions is required for an accurate insight into Epo signaling. We recently developed a mammalian protein-protein interaction trap (MAPPIT), a cytokine receptorbased 2-hybrid method that operates in intact Hek293-T mammalian cells. As baits, we used intracellular segments of the EpoR containing 1 or 2 tyrosines. Several known signaling molecules, including cytokine-inducible SH2-containing protein (CIS), suppressor of cytokine signaling-2 (SOCS2), phosphatidylinositol 3-kinase (PI3-K), phospholipase C-␥ (PLC-␥), and signal transducer and activator of transcription 5 (STAT5) were used as prey. We also extended the MAPPIT method to enable interaction analysis with wild-type EpoR. In this relay MAPPIT approach, instead of using isolated EpoR fragments as bait, we used the full-length EpoR itself as a "receptor bait." Finally, we introduced MAPPIT in the erythroleukemic TF-1 cell line, which is a more natural setting of the EpoR. With these strategies several known interactions with the EpoR were analyzed and evidence for new interactions was obtained. IntroductionThe glycoprotein hormone erythropoietin (Epo) is essential for red blood cell development because Epo Ϫ/Ϫ and Epo receptor-deficient (EpoR Ϫ/Ϫ ) mice die at an embryonic stage due to severe anemia. 1 Binding of Epo to its receptor prevents apoptosis of erythroid progenitors and promotes proliferation and erythroid maturation. The EpoR is a member of the type I cytokine receptor family 2 characterized by a single ligand-binding cytokine receptor homology domain 3 containing conserved cysteines and a Trp-Ser-X-Trp-Ser motif, 4 and lacking any catalytic activity in the intracellular region. 2 Epo binding to its receptor induces a conformational change of the preformed receptor-dimer resulting in activation and cross-phosphorylation of associated Janus kinase 2 (JAK2) tyrosine kinases. 5 Activated JAK2 molecules then phosphorylate tyrosine residues in the cytosolic tail of the EpoR that serve as docking sites for signaling molecules, thereby leading to the activation of several intracellular pathways. 6,7 These signaling molecules are often phosphorylated by JAK2 or other kinases such as Lyn. 8 Activation of the EpoR can lead to both antiapoptotic and proliferative effects. For example, signal transducers and activators of transcription 5a and 5b (STAT5a/b) bind to multiple phosphorylated tyrosine motifs (pYs) on the receptor, including pY344 and pY402. [9][10][11] On tyrosine phosphorylation by JAK2, STAT5 molecules translocate as dimers to the nucleus where they promote transcription of target genes including the antiapoptotic Bcl xL gene. 12 Several pathways have been described that independently lead to Epo-induced activation of phosphatidylinositol 3Ј-kinase (PI3-K) and phosphorylation of its downstream effectors. The p85 subunit of PI3-K directly associates ...

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SH2-Containing Protein Tyrosine Phosphatase-1 (SHP-1) Association with Jak2 in UT-7/Epo Cells

Cited by 12 publications

References 28 publications

Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

SHP1 tyrosine phosphatase negatively regulates NPM-ALK tyrosine kinase signaling

A systematic scan of interactions with tyrosine motifs in the erythropoietin receptor using a mammalian 2-hybrid approach

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