Crystal Structure of a Complex between Protein Tyrosine Phosphatase 1B and the Insulin Receptor Tyrosine Kinase

Li, Shiqing; Depetris, Rafael S.; Barford, David; Chernoff, Jonathan; Hubbard, Stevan R.

doi:10.1016/j.str.2005.07.019

Cited by 46 publications

(39 citation statements)

References 47 publications

(58 reference statements)

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“…This is consistent with the idea that pseudokinases have evolved away from catalysis to adopt roles such as protein-protein interaction (16,31,32). Instead, the region of ROP5 that binds IRGa6 is the face sometimes recognized by specific kinase regulatory proteins (33). Specificity at this surface is achieved by discrimination of three-dimensional structure rather than simply primary sequence (as is typical in substrate recognition).…”

Section: The Rop5-irga6 Interface Is Distal From the Protein Activesupporting

confidence: 81%

The Toxoplasma Pseudokinase ROP5 Is an Allosteric Inhibitor of the Immunity-related GTPases

Reese

Shah

Boothroyd

2014

Journal of Biological Chemistry

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Background:Competition between pathogens and their hosts drives the evolution of molecules that give either organism an edge. Results: Structural and biochemical data show how the parasite pseudokinase ROP5 inhibits the murine GTPase IRGa6. Conclusion: The surfaces of both ROP5 and IRG proteins that interact in the complex are under strong selective pressure. Significance: This highlights an extreme case of evolutionary competition.

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Section: The Rop5-irga6 Interface Is Distal From the Protein Activesupporting

confidence: 81%

The Toxoplasma Pseudokinase ROP5 Is an Allosteric Inhibitor of the Immunity-related GTPases

Reese

Shah

Boothroyd

2014

Journal of Biological Chemistry

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“…Consistent with this notion, previous studies have shown that PTP1B may interact with unphosphorylated proteins through its carboxy-terminal prolinerich motif, 40,41 whereas other have reported that PTP1B may interact with the insulin receptor via the PTP1B catalytic domain but independent of its active site. 42 Alternatively, but not mutually exclusive, it is also possible that binding in resting cells may reflect the ongoing process of phosphorylation by JAK PTKs and dephosphorylation by PTP1B. A similar interaction was not seen previously for TCPTP and STAT6 in unstimulated cells, 11 consistent with the notion that TCPTP acts on STAT6 in the nucleus.…”

supporting

confidence: 72%

PTP1B is a negative regulator of interleukin 4–induced STAT6 signaling

Malumbres

Shields

et al. 2008

Blood

113

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Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed enzyme shown to negatively regulate multiple tyrosine phosphorylation-dependent signaling pathways. PTP1B can modulate cytokine signaling pathways by dephosphorylating JAK2, TYK2, and STAT5a/b. Herein, we report that phosphorylated STAT6 may serve as a cytoplasmic substrate for PTP1B. Overexpression of PTP1B led to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B knockdown or deficiency augmented IL-4-induced STAT6 signaling. Pretreatment of these cells with the PTK inhibitor staurosporine led to sustained STAT6 phosphorylation consistent with STAT6 serving as a direct substrate of PTP1B. Furthermore, PTP1B-D181A "substrate-trapping" mutants formed stable complexes with phosphorylated STAT6 in a cellular context and endogenous PTP1B and STAT6 interacted in an interleukin 4 (IL-4)-inducible manner. We delineate a new negative regulatory loop of IL-4-JAK-STAT6 signaling. We demonstrate that IL-4 induces PTP1B mRNA expression in a phosphatidylinositol 3-kinase-dependent manner and enhances PTP1B protein stability to suppress IL-4-induced STAT6 signaling. Finally, we show that PTP1B expression may be preferentially elevated in activated B cell-like diffuse large B-cell lymphomas. These observations identify a novel regulatory loop for the regulation of IL-4-induced STAT6 signaling that may have important implications in both neoplastic and inflammatory processes. IntroductionInterleukin 4 (IL-4) is a type I cytokine that has an important role in the regulation of Th2 cells and B cells during an immune response. IL-4 regulates cellular differentiation, proliferation, and apoptosis and plays an important role in the pathogenesis of allergic and autoimmune diseases. 1,2 Furthermore, recent studies have suggested that IL-4 signaling may have an important role in neoplastic diseases. IL-4 may affect malignant cells and can elicit potent antitumor activity against carcinoma and lymphoma cell lines in vitro and in animal models. [3][4][5][6] We have recently demonstrated qualitatively different IL-4 effects on gene expression, cell proliferation, and intracellular signaling in germinal center B-cell (GCB)-like versus activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCLs). 7 Further, our preliminary data have suggested that IL-4 may enhance chemotherapy and complementdependent rituximab-mediated cytotoxicities in GCB-like but not in ABC-like DLBCLs. 8 The pleiotropic but specific effects of IL-4 on different cell types result from the activation of distinct signaling pathways that are tightly regulated. 1 IL-4 signaling is initiated when the cytokine binds its cell surface receptor activating receptor-associated Janusactivated protein kinases (JAKs) that phosphorylate specific tyrosine residues in the IL-4R␣ chain. This is followed by recruitment and phosphorylation of signal transducer and activator of transcription 6 (STAT6) and insulin receptor substance-2 (IRS-2), and activation of phosphatidylin...

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“…(The function of this extra helix has not been established, but in the structure of a complex between IRK and the protein tyrosine phosphatase PTP1B (Li et al 2005), this helix is part of the phosphatase binding site.) Tyrosine kinase activity is regulated by the phosphorylation state of the activation loop in the C lobe, which begins with the kinase-conserved 1150 DFG motif and ends with a conserved proline (P1172).…”

Section: Insr Three-dimensional Structurementioning

confidence: 99%

“…A crystal structure of a complex between PTP1B and phosphorylated IRK was determined (Li et al 2005), which revealed an unusual mode of interaction. Rather than binding to the phosphorylated activation loop, PTP1B was bound to the "backside" of IRK.…”

Section: Recruitment Of Negative Regulators To the Activated Insrmentioning

confidence: 99%

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Hubbard

2013

Cold Spring Harbor Perspectives in Biology

123

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Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular a subunits and two membrane-spanning, tyrosine kinase-containing b subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans-phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine-binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR's catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop.

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Crystal Structure of a Complex between Protein Tyrosine Phosphatase 1B and the Insulin Receptor Tyrosine Kinase

Cited by 46 publications

References 47 publications

The Toxoplasma Pseudokinase ROP5 Is an Allosteric Inhibitor of the Immunity-related GTPases

The Toxoplasma Pseudokinase ROP5 Is an Allosteric Inhibitor of the Immunity-related GTPases

PTP1B is a negative regulator of interleukin 4–induced STAT6 signaling

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

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