Selective regulation of tumor necrosis factor–induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase

Vliet, Catherine Julia van; Bukczynska, Patricia; Puryer, Michelle A; Sadek, Christine M.; Shields, Benjamin; Tremblay, Michel L.; Tiganis, Tony

doi:10.1038/ni1169

Cited by 148 publications

(139 citation statements)

References 54 publications

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“…Our observations are in line with previously proposed roles for these phosphatases. PTP1B activates c-Src by dephophorylating Tyr 527 (39,40), whereas TCPTP inactivates c-Src by dephosporylating Tyr 416 (41). Consistent with published observations, knockdown of PTP1B in MIN6 cells led to increased Tyr 527 phosphorylation (SFK inactivation), whereas TCPTP knockdown led to .…”

Section: Discussionsupporting

confidence: 80%

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Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

Bettaieb

Liu

et al. 2011

Journal of Biological Chemistry

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Protein-tyrosine phosphatase 1B (PTP1B) and T cell proteintyrosine phosphatase (TCPTP) are closely related intracellular phosphatases implicated in the control of glucose homeostasis. PTP1B and TCPTP can function coordinately to regulate protein tyrosine kinase signaling, and PTP1B has been implicated previously in the regulation of endoplasmic reticulum (ER) stress. In this study, we assessed the roles of PTP1B and TCPTP in regulating ER stress in the endocrine pancreas. PTP1B and TCPTP expression was determined in pancreases from chow and high fat fed mice and the impact of PTP1B and TCPTP overor underexpression on palmitate-or tunicamycin-induced ER stress signaling assessed in MIN6 insulinoma ␤ cells. PTP1B expression was increased, and TCPTP expression decreased in pancreases of mice fed a high fat diet, as well as in MIN6 cells treated with palmitate. PTP1B overexpression or TCPTP knockdown in MIN6 cells mitigated palmitate-or tunicamycininduced PERK/eIF2␣ ER stress signaling, whereas PTP1B deficiency enhanced ER stress. Moreover, PTP1B deficiency increased ER stress-induced cell death, whereas TCPTP deficiency protected MIN6 cells from ER stress-induced death. ER stress coincided with the inhibition of Src family kinases (SFKs), which was exacerbated by PTP1B overexpression and largely prevented by TCPTP knockdown. Pharmacological inhibition of SFKs ameliorated the protective effect of TCPTP deficiency on ER stress-induced cell death. These results demonstrate that PTP1B and TCPTP play nonredundant roles in modulating ER stress in pancreatic ␤ cells and suggest that changes in PTP1B and TCPTP expression may serve as an adaptive response for the mitigation of chronic ER stress.

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Section: Discussionsupporting

confidence: 80%

“…Antibodies used in this study (source, species, and conditions for use) are listed in supplemental Table S1. c-Src Y527F-pJ3⍀ and c-Src WT-pJ3⍀ have been described previously (41). Unless otherwise indicated, chemicals were purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

Bettaieb

Liu

et al. 2011

Journal of Biological Chemistry

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“…Interestingly, a recent report has identified a role for a PTP1B-related phosphatase, T cell protein-tyrosine phosphatase, in the negative regulation of ERK1/2 activity downstream from the TNF receptor, through dephosphorylation and inactivation of the Src kinase (70). In contrast, PTP1B has been proposed to activate Src in fibroblasts through dephosphorylation of a negative regulatory site on Src (pY 527 ) (9).…”

Section: Discussionmentioning

confidence: 99%

Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

Sangwan

Paliouras

Cheng

et al. 2006

Journal of Biological Chemistry

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Genetic disruption of protein-tyrosine phosphatase 1B (PTP1B) in mice leads to increased insulin sensitivity and resistance to weight gain. Although PTP1B has been implicated as a regulator of multiple signals, its function in other physiological responses in vivo is poorly understood. Here we demonstrate that PTP1B-null mice are resistant to Fas-induced liver damage and lethality, as evident by reduced hepatic apoptosis in PTP1B-null versus wild type mice and reduced levels of circulating liver enzymes. Activation of pro-apoptotic caspases-8, -9, -3, and -6 was attenuated in livers from PTP1B-null mice following Fas receptor stimulation, although components of the death-inducing signaling complex were intact. Activation of anti-apoptotic regulators, such as the hepatocyte growth factor/Met receptor tyrosine kinase, as well as Raf, ERK1/2, FLIP L , and the NF-B pathway, was elevated in response to Fas activation in livers from PTP1B-null mice. Using PTP1B-deficient primary hepatocytes, we show that resistance to Fas-mediated apoptosis is cell autonomous and that signals involving the Met, ERK1/2, and NF-B pathways are required for cytoprotection. This study identifies a previously unknown physiological role for PTP1B in Fas-mediated liver damage and points to PTP1B as a potential therapeutic target against hepatotoxic agents.

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“…Thus, our results point towards PTPN2 tuning T-cell responses to antigen in the periphery for the maintenance of peripheral tolerance. Although PTPN2 has the capacity to regulate both TCRmediated signalling, through the dephosphorylation of SFKs 23,49,50 , and IL-7/IL-15-mediated signalling, through the dephosphorylation of JAK1/3 and STAT5 (refs 37,38), our studies are consistent with the effects of PTPN2 deficiency on CD8 þ T-cell LIP at least being independent of cytokine signalling, since (1) IL-7 signalling was not enhanced by PTPN2 deficiency in naive T cells, (2) IL-7/IL-15 signalling was not enhanced by PTPN2 deficiency in memory T cells, (3) PTPN2 deficiency did not alter CD8 þ memory T cell LIP and (4) PTPN2 deficiency did not alter OT-I CD8 þ naive T-cell LIP, despite OT-I T cells being reliant on IL-7 (ref. 51).…”

Section: Discussionmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

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Selective regulation of tumor necrosis factor–induced Erk signaling by Src family kinases and the T cell protein tyrosine phosphatase

Cited by 148 publications

References 54 publications

Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

Differential Regulation of Endoplasmic Reticulum Stress by Protein Tyrosine Phosphatase 1B and T Cell Protein Tyrosine Phosphatase

Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

PTPN2 attenuates T-cell lymphopenia-induced proliferation

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