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

Townley, Richard; Shen, Shi-Hsiang; Banville, Denis; Ramachandran, Chidambaram

doi:10.1021/bi00212a006

Cited by 85 publications

(51 citation statements)

References 22 publications

(31 reference statements)

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“…Cbl is a substrate of SHP-1 (18), and SHP-1 activity is regulated by allosteric mechanisms involving interaction of its Src homology 2 domain with other proteins (19,20). We wondered whether dephosphorylation of Cbl after EphB6 cross-linking was related to changes in the interaction between Cbl and SHP-1.…”

Section: Interaction Between Ephb6 and Cblmentioning

confidence: 99%

Cross-Linking of EphB6 Resulting in Signal Transduction and Apoptosis in Jurkat Cells

Luo

Wan

et al. 2001

The Journal of Immunology

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Eph kinases are the largest family of receptor tyrosine kinases (RTK), and their ligands are cell surface molecules. The known functions of Eph kinases are mainly pattern formation in the CNS. Although several Eph kinases are expressed at high levels in hemopoietic cells and in the thymus, we have no knowledge of the functions of any Eph kinase in the immune system. In this study, we have demonstrated that an Eph kinase, EphB6, was expressed at high levels in Jurkat leukemic T cells. Co-cross-linking of EphB6 and CD3 led to an altered profile of lymphokine secretion along with proliferation inhibition of Jurkat cells. The cells subsequently underwent Fas-mediated apoptosis. Although EphB6 has no intrinsic kinase activity, its cross-linking triggered general protein tyrosine phosphorylation in Jurkat cells. EphB6 was found to associate with a number of molecules in the signaling pathways, notably Cbl. EphB6 cross-linking resulted in Cbl dephosphorylation and dissociation from Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1). Our results show that EphB6 has important functions in T cells, and it can transduce signals into the cells via proteins it associates with.

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Section: Interaction Between Ephb6 and Cblmentioning

confidence: 99%

Cross-Linking of EphB6 Resulting in Signal Transduction and Apoptosis in Jurkat Cells

Luo

Wan

et al. 2001

The Journal of Immunology

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“…24,25 SHP1 has been shown to silence the JAK/STAT pathway by dephosphorylating and inactivating JAK. [26][27][28][29] SHP1 has been reported to have tumor suppressor function. 30 In a previous study, we demonstrated that loss of SHP1 expression related to gene methylation is found in ALK þ ALCL cell lines and is detectable in the majority of ALK þ ALCL tumors.…”

Section: Introductionmentioning

confidence: 99%

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

et al. 2006

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Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALK þ ALCL) is characterized by constitutive activation of the Janus kinase (JAK)3/signal transducers and activators of transcription 3 (STAT3) signaling pathway. SHP1, a tyrosine phosphatase that negatively regulates JAK/STAT, is frequently absent in ALK þ ALCL owing to gene methylation. To test the hypothesis that loss of SHP1 contributes to JAK3/ STAT3 activation in ALK þ ALCL cells, we induced SHP1 expression using 5-aza-2 0 -deoxycytidine (5-AZA), an inhibitor of DNA methyltransferase, in ALK þ ALCL cell lines, and correlated with changes in the JAK3/STAT3 pathway. 5-AZA gradually restored SHP1 expression in Karpas 299 and SU-DHL-1 cells over 5 days. The initially low level of SHP1 expression did not result in significant changes to the expression or tyrosine phosphorylation of JAK3 and STAT3. However, higher levels of SHP1 seen subsequently correlated with substantial decreases in JAK3 and pJAK3, followed by pSTAT3 (but not STAT3). Importantly, the decrease in JAK3 was abrogated by MG132, a proteasome inhibitor. 5-AZA induced no significant increase in apoptosis but it sensitized ALCL cells to doxorubicin-induced apoptosis. Our findings support the concept that loss of SHP1 contributes to the constitutive activation of JAK3/STAT3 in ALK þ ALCL cells. SHP1 appears to downregulate JAK3 by two mechanisms: tyrosine dephosphorylation and increased degradation via the proteasome pathway.

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“…SHP-1 is composed of a central catalytic domain, two SH2 domains at its N terminus, and a C terminus with potential tyrosine phosphorylation sites (23). The SH2 domains have been shown to be important for localization (24 -34) as well as for the regulation of SHP-1 catalytic activity (35,36). In vitro data suggest that the C terminus may also be involved in regulating the phosphatase activity of SHP-1 (reviewed in Ref.…”

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confidence: 99%

Identification of a Novel Lipid Raft-Targeting Motif in Src Homology 2-Containing Phosphatase 1

Sankarshanan

Iype

et al. 2007

The Journal of Immunology

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The tyrosine phosphatase Src homology 2-containing phosphatase 1 (SHP-1) is a key negative regulator of TCR-mediated signaling. Previous studies have shown that in T cells a fraction of SHP-1 constitutively localizes to membrane microdomains, commonly referred to as lipid rafts. Although this localization of SHP-1 is required for its functional regulation of T cell activation events, how SHP-1 is targeted to the lipid rafts was unclear. In this study, we identify a novel, six-amino acid, lipid raft-targeting motif within the C terminus of SHP-1 based on several biochemical and functional observations. First, mutations of this motif in the context of full-length SHP-1 result in the loss of lipid raft localization of SHP-1. Second, this motif alone restores raft localization when fused to a mutant of SHP-1 (SHP-1 ΔC) that fails to localize to rafts. Third, a peptide encompassing the 6-mer motif directly binds to phospholipids whereas a mutation of this motif abolishes lipid binding. Fourth, whereas full-length SHP-1 potently inhibits TCR-induced tyrosine phosphorylation of specific proteins, expression of a SHP-1-carrying mutation within the 6-mer motif does not. Additionally, although SHP-1 ΔC was functionally inactive, the addition of the 6-mer motif restored its functionality in inhibiting TCR-induced tyrosine phosphorylation. Finally, this 6-mer mediated targeting of SHP-1 lipid rafts was essential for the function of this phosphatase in regulating IL-2 production downstream of TCR. Taken together, these data define a novel 6-mer motif within SHP-1 that is necessary and sufficient for lipid raft localization and for the function of SHP-1 as a negative regulator of TCR signaling.

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

Cited by 85 publications

References 22 publications

Cross-Linking of EphB6 Resulting in Signal Transduction and Apoptosis in Jurkat Cells

Cross-Linking of EphB6 Resulting in Signal Transduction and Apoptosis in Jurkat Cells

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

Identification of a Novel Lipid Raft-Targeting Motif in Src Homology 2-Containing Phosphatase 1

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