Functional Abnormalities in Protein Tyrosine Phosphatase ε-Deficient Macrophages

Sully, Veronica; Pownall, Scott; Vincan, Elizabeth; Bassal, Sahar; Borowski, Anita; Hart, Prue H.; Rockman, Steven; Phillips, Wayne A.

doi:10.1006/bbrc.2001.5360

Cited by 34 publications

(26 citation statements)

References 23 publications

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“…This effect correlates in vivo with delayed myelination of sciatic nerve axons in young PTPε-deficient mice (33,40,41) and with delayed optic nerve myelination in mice expressing a "substrate-trapping" mutant of RPTPε (29). cyt-PTPε can also downregulate signaling mediated by the mitogen-activated protein kinase (42,45) and JAK-STAT (37-39) pathways and is required for proper functioning of mouse macrophages (35).…”

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confidence: 92%

Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

Sines

Granot-Attas

Weisman-Welcher

et al. 2007

Molecular and Cellular Biology

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Protein tyrosine phosphatases (PTPs) are key mediators that link physiological cues with reversible changes in protein structure and function; nevertheless, significant details concerning their regulation in vivo remain unknown. We demonstrate that PTP associates with microtubules in vivo and is inhibited by them in a noncompetitive manner. Microtubule-associated proteins, which interact strongly with microtubules in vivo, significantly increase binding of PTP to tubulin in vitro and further reduce phosphatase activity. Conversely, disruption of microtubule structures in cells reduces their association with PTP, alters the subcellular localization of the phosphatase, and increases its specific activity. Activation of the epidermal growth factor receptor (EGFR) increases the PTP-microtubule association in a manner dependent upon EGFR-induced phosphorylation of PTP at Y638 and upon microtubule integrity. These events are transient and occur with rapid kinetics similar to EGFR autophosphorylation, suggesting that activation of the EGFR transiently down-regulates PTP activity near the receptor by promoting the PTP-microtubule association. Tubulin also inhibits the tyrosine phosphatase PTP1B but not receptor-type PTP or the unrelated alkaline phosphatase. The data suggest that reversible association with microtubules is a novel, physiologically regulated mechanism for regulation of tyrosine phosphatase activity in cells.Reversible phosphorylation of tyrosine residues in proteins is a major regulator of protein structure and function. Tyrosine phosphorylation of proteins is regulated in part by the activity of members of the protein tyrosine phosphatase (PTP) superfamily, which currently includes over 100 genes in higher organisms. Of these, 38 genes encode "classical" tyrosine phosphatases (PTPs), which are strictly specific for phosphotyrosine. Products of this gene family all contain one or two copies of the PTP domain and are either receptor-type integral membrane proteins or non-receptor-type proteins (1, 3).The numbers of known tyrosine kinases and tyrosine phosphatases are similar and small compared to the numbers and complexities of their potential substrates (1). The apparent contradiction between this and the high degree of specificity that exists in signaling processes in vivo has made understanding the mechanisms by which PTP activity is regulated of paramount importance. PTP genes often produce several distinct protein products by alternative splicing or use of alternative promoters (3). At the protein level, PTP activity can be inhibited by dimerization (e.g., see references 22, 23, and 43) or by reversible oxidation of the key cysteine residue in the PTP catalytic domain (9, 44). Proteolysis and phosphorylation, which can affect subcellular localization, conformation, or the ability to bind other proteins can also activate or inhibit PTPs (e.g., see references 6, 13, 17, 48, and 49). Regulation of PTP activity by binding of extracellular ligands to receptor-type PTPs (RPTPs), which inhibits PTP activity...

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confidence: 92%

Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

Sines

Granot-Attas

Weisman-Welcher

et al. 2007

Molecular and Cellular Biology

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“…PTP⑀-deficient mice develop normally, breed well and are fertile, although they show functional abnormalities in bone marrow-derived macrophages (19) and defects in osteoclast subcellular organization and function (20). Abnormalities in cellular morphology, together with reduced intracellular K ϩ content and increased Ca 2ϩ -activated K ϩ channel activity were also documented in red cells from PTP⑀-deficient mice (21).…”

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confidence: 99%

Epidermal Growth Factor Receptor (EGFR)-mediated Positive Feedback of Protein-tyrosine Phosphatase ϵ (PTPϵ) on ERK1/2 and AKT Protein Pathways Is Required for Survival of Human Breast Cancer Cells

Nunes‐Xavier

Elson

Pulido

2012

Journal of Biological Chemistry

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Background:To investigate the functional role of PTP⑀ in human breast cancer cell lines. Results: PTP⑀ was up-regulated in human breast cancer cells in an EGFR-and ERK1/2-dependent manner. PTP⑀ displayed a positive role in survival of human breast cancer cells. Conclusion: PTP⑀ generates a positive feedback regulatory loop required for survival of human breast cancer cells. Significance: PTP⑀ could be a putative target in breast cancer treatment.Increased tyrosine phosphorylation has been correlated with human cancer, including breast cancer. In general, the activation of tyrosine kinases (TKs) can be antagonized by the action of protein-tyrosine phosphatases (PTPs). However, in some cases PTPs can potentiate the activation of TKs. In this study, we have investigated the functional role of PTP⑀ in human breast cancer cell lines. We found the up-regulation and activation of receptor PTP⑀ (RPTP⑀) in MCF-7 cells and MDA-MB-231 upon PMA, FGF, and serum stimulation, which depended on EGFR and ERK1/2 activity. Diminishing the expression of PTP⑀ in human breast cancer cells abolished ERK1/2 and AKT activation, and decreased the viability and anchorage-independent growth of the cells. Conversely, stable MCF-7 cell lines expressing inducible high levels of ectopic PTP⑀ displayed higher activation of ERK1/2 and anchorage-independent growth. Our results demonstrate that expression of PTP⑀ is up-regulated and activated in breast cancer cell lines, through EGFR, by sustained activation of the ERK1/2 pathway, generating a positive feedback regulatory loop required for survival of human breast cancer cells.

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“…cyt-PTP⑀ dephosphorylates the delayed rectifier, voltage-gated potassium channels Kv2.1 and Kv1.5 in Schwann cells, a finding that correlates with severe transient hypomyelination of sciatic nerve axons in young PTP⑀-deficient mice (26). PTP⑀ also suppresses endothelial cell proliferation (27), is required for proper functioning of mouse macrophages (28), and inhibits JAK (Janus kinase)-STAT (signal transducers and activators of transcription) signaling in M1 leukemia cells in response to various cytokines (29,30). p67 PTP⑀ , which is produced by internal initiation of translation from PTP⑀ mRNAs, and p65 PTP⑀ , which is produced by calpain-mediated proteolytic processing of the larger PTP⑀ forms, are N-terminally truncated forms of PTP⑀ and are exclusively cytosolic.…”

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confidence: 99%

Tyrosine Phosphatase-ε Activates Src and Supports the Transformed Phenotype of Neu-induced Mammary Tumor Cells

Gil-Henn

Elson

2003

Journal of Biological Chemistry

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Functional Abnormalities in Protein Tyrosine Phosphatase ε-Deficient Macrophages

Cited by 34 publications

References 23 publications

Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

Epidermal Growth Factor Receptor (EGFR)-mediated Positive Feedback of Protein-tyrosine Phosphatase ϵ (PTPϵ) on ERK1/2 and AKT Protein Pathways Is Required for Survival of Human Breast Cancer Cells

Tyrosine Phosphatase-ε Activates Src and Supports the Transformed Phenotype of Neu-induced Mammary Tumor Cells

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