TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation

Kim, Young Sik; Seo, Dong Wan; Kong, Su Kang; Lee, Ju Han; Lee, Eung Seok; Stetler‐Stevenson, Maryalice; Stetler‐Stevenson, William G.

doi:10.1016/j.canlet.2008.04.020

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…26 However, after TIMP-1 stimulation of germinal center B cells SHP-1 is translocated to the nucleus. 25 This is in agreement with our finding showing that endorepellin stimulation leads to nuclear translocation of SHP-1 in the myogenic ␣2␤1 ϩ C2C12. Nuclear SHP-1 could dephosphorylate key transcription factors, such as STAT3, 25,26 but the precise effect of nuclear SHP-1 remains to be clarified.…”

supporting

confidence: 83%

“…25 This is in agreement with our finding showing that endorepellin stimulation leads to nuclear translocation of SHP-1 in the myogenic ␣2␤1 ϩ C2C12. Nuclear SHP-1 could dephosphorylate key transcription factors, such as STAT3, 25,26 but the precise effect of nuclear SHP-1 remains to be clarified.A novel result of our study was the decline of SHP-1 levels in liver, kidney, and spleen from ␣2␤1-null animals, in addition to the pulmonary microvascular endothelial cells. Moreover, tyrosine phosphatase activity from SHP-1 immunoprecipitated from the liver of ␣2␤1 Ϫ/Ϫ mice was also significantly reduced.…”

supporting

confidence: 83%

“…Endorepellin signaling induces translocation of SHP-1 into the nuclei SHP-1 can translocate into the nuclei 25 where it can regulate transcription of early response genes. 26 We tested wild-type and integrin ␣1-and ␣2-transfected C2C12 cells, which show high expression of SHP-1.…”

Section: Org Frommentioning

confidence: 99%

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Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity

Nyström

Shaik

Gullberg

et al. 2009

Blood

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Endorepellin, the C-terminal domain of perlecan, is a powerful angiogenesis inhibitor. To dissect the mechanism of endorepellin-mediated endothelial silencing, we used an antibody array against multiple tyrosine kinase receptors. Endorepellin caused a widespread reduction in phosphorylation of key receptors involved in angiogenesis and a concurrent increase in phosphatase activity in endothelial cells and tumor xenografts. These effects were efficiently hampered by function-blocking antibodies against integrin ␣2␤1, the functional endorepellin receptor. The Src homology-2 protein phosphatase-1 (SHP-1) coprecipitated with integrin ␣2 and was phosphorylated in a dynamic fashion after endorepellin stimulation. Genetic evidence was provided by lack of an endorepellin-evoked phosphatase response in microvascular endothelial cells derived from integrin ␣2␤1 ؊/؊ mice and by response to endorepellin in cells genetically engineered to express the ␣2␤1 integrin, but not in cells either lacking this receptor or expressing a chimera harboring the integrin ␣2 ectodomain fused to the ␣1 intracellular domain. siRNA-mediated knockdown of integrin ␣2 caused a dose-dependent reduction of SHP-1. Finally, the levels of SHP-1 and its enzymatic activity were substantially reduced in multiple organs from ␣2␤1 ؊/؊ mice. Our results show that SHP-1 is an essential mediator of endorepellin activity and discover a novel functional interaction between the integrin ␣2 subunit and SHP-1. (Blood. 2009; 114:4897-4906) IntroductionThe development and maintenance of an efficient vascular system is vital for organ function and health in all higher organisms. Angiogenesis is abundant during fetal development but in the adult is a rare process mainly restricted to the female reproductive cycle and wound healing. However, deregulated angiogenesis is a prominent factor in many major diseases such as cancer, diabetes, and ischemia occurring after stroke. Controlled angiogenesis is achieved by interplay of proangiogenic and antiangiogenic factors. Proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), signal by their respective receptor tyrosine kinase (RTK) to stimulate endothelial cell migration and proliferation, whereas angiogenic inhibitors counteract these actions. 1 The list of reported negative regulators of angiogenesis is long, ever growing, and truly versatile. Nevertheless, a common theme for many of them is that they are derived from limited proteolysis of extracellular matrix components and that they interact with integrin receptors. 2 The angiostatic protein endorepellin, located within the C-terminus of the heparan sulfate proteoglycan perlecan, consists of 3 laminin globular (LG1-3) domains separated by 4 epidermal growth factor-like repeats. 3 Endorepellin exerts its activity by a noncanonical cation-independent binding of the LG3 domain to the ␣2 I domain of the integrin ␣2␤1, 4-7 a key receptor regulating angiogenesis. [8][9][10] This triggers a signaling cascade that leads to endothelial cell immobilizatio...

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supporting

confidence: 83%

supporting

confidence: 83%

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Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity

Nyström

Shaik

Gullberg

et al. 2009

Blood

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“…S9). 5) On the basis of previous works (30,31), and because we could coimmunoprecipitate SHP1 with STAT5 and detect it by immunoblotting and MS analysis ( Supplementary Fig. S10), we assume that SHP1 is responsible for the dephosphorylation of pSTAT5.…”

Section: Quick Guide To Main Model Equationsmentioning

confidence: 90%

Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

et al. 2011

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Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor a, JAK2, and STAT5, but not of STAT6. Genomewide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. Cancer Res; 71(3); 693-704. Ó2010 AACR.

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“…According to the previous findings of MIF blocking the cytotoxic T lymphocyte (CTL) response and CD44 being essential for MIF/CD74 complex signalling, this interaction has been proposed as a potential strategy of the malignant cells to evade cytotoxic killing [127]. Another hypothesis provided suggests tissue inhibitory of metalloproteinase 1 (TIMP1) in cooperation with CD44 to rescue pre-apoptotic defect B cells in B cell malignancies as HL [128].…”

Section: Hodgkin Lymphomamentioning

confidence: 99%

CD44 in hematological neoplasias

2011

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TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation

Cited by 13 publications

References 37 publications

Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity

Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity

Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

CD44 in hematological neoplasias

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