Protein Tyrosine Phosphatase α Regulates Fyn Activity and Cbp/PAG Phosphorylation in Thymocyte Lipid Rafts

Maksumova, Lola; Le, Hoa; Muratkhodjaev, Farkhad; Davidson, Dominique; Veillette, André; Pallen, Catherine J.

doi:10.4049/jimmunol.175.12.7947

Cited by 46 publications

(55 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to its effect on Fyn, PTP␣ did not significantly affect the phosphorylation state of Lck, in accordance with the finding that Fyn but not Lck activity is altered in PTP␣-null thymocytes (16). This may reflect a difference in location rather than a difference in substrate specificity as PTP␣ has been shown to specifically affect the activity of Fyn in lipid rafts (16).…”

Section: Discussioncontrasting

confidence: 39%

“…This may reflect a difference in location rather than a difference in substrate specificity as PTP␣ has been shown to specifically affect the activity of Fyn in lipid rafts (16). In that and in the present study, radioimmune precipitation assay buffer was used to solubilize Fyn from lipid rafts.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, examination of thymocytes from PTP␣-null mice revealed that Fyn and the potential Fyn substrate Cbp were hyperphosphorylated (16). Fyn was hyperphosphorylated at both the negative and positive regulatory sites in PTP␣ Ϫ/Ϫ thymocytes and was more active than Fyn from wild-type mouse thymocytes in an in vitro assay (16). Consistent with these findings, in the present study we observe that the overexpression of PTP␣ in CD45 Ϫ T cells induces the dephosphorylation of Fyn and its substrate, Cbp.…”

Section: Discussionmentioning

confidence: 99%

“…A comparison of CD45 and PTP␣ activities revealed that PTP␣ was a much less active PTP under the in vitro conditions tested. Furthermore, analysis of thymocyte development and T cell acti-vation in PTP␣ Ϫ/Ϫ mice revealed a role for PTP␣ in the dephosphorylation and regulation of lipid raft-associated Fyn and its substrate, Cbp (16). This raises the possibility that both CD45 and PTP␣ contribute to the regulation of SFKs in T cells, and this study was performed to evaluate the contributions of each phosphatase.…”

Section: Although Expression Of Ptp␣ In a Cd45mentioning

confidence: 99%

“…Cell lysates were incubated on ice for 20 min and then centrifuged at 14,000 ϫ g for 10 min at 4°C. PTP␣, Fyn, Lck, Cbp, or Pyk2 was immunoprecipitated from CD45 ϩ and CD45 Ϫ T cells, thymocytes, or splenocytes, essentially as described previously (9,15,16). Samples were analyzed on 10% acrylamide gels by SDS-PAGE and transferred to polyvinylidene difluoride (PVDF) membrane (Immobilon P, Millipore).…”

Section: Cells-bw5147 Cd45mentioning

confidence: 99%

See 4 more Smart Citations

Differential Function of PTPα and PTPα Y789F in T Cells and Regulation of PTPα Phosphorylation at Tyr-789 by CD45

Maksumova

Wang

Wong

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

CD45 is a major membrane protein tyrosine phosphatase (PTP) expressed in T cells where it regulates the activity of Lck, a Src family kinase important for T cell receptor-mediated activation. PTP␣ is a more widely expressed transmembrane PTP that has been shown to regulate the Src family kinases, Src and Fyn, and is also present in T cells. Here, PTP␣ was phosphorylated at Tyr-789 in CD45؊ T cells but not in CD45 ؉ T cells suggesting that CD45 could regulate the phosphorylation of PTP␣ at this site. Furthermore, CD45 could directly dephosphorylate PTP␣ in vitro. Expression of PTP␣ and PTP␣-Y789F in T cells revealed that the mutant had a reduced ability to decrease Fyn and Cbp phosphorylation, to regulate the kinase activity of Fyn, and to restore T cell receptor-induced signaling events when compared with PTP␣. Conversely, this mutant had an increased ability to prevent Pyk2 phosphorylation and CD44-mediated cell spreading when compared with PTP␣. These data demonstrate distinct activities of PTP␣ and PTP␣-Y789F in T cells and identify CD45 as a regulator of PTP␣ phosphorylation at tyrosine 789 in T cells. Protein tyrosine phosphatases (PTPs) 5, together with protein tyrosine kinases, are responsible for controlling the level of tyrosine phosphorylation within cells. In general, basal tyrosine phosphorylation levels in unstimulated cells are relatively low, suggesting that protein tyrosine phosphatase activity prevails over tyrosine kinase activities under resting conditions. Stimulation of cells via a variety of receptors linked to tyrosine kinases can induce tyrosine phosphorylation cascades that lead to cell activation or modulation of cellular function. In T lymphocytes, CD45 is a major protein tyrosine phosphatase expressed at the T cell membrane where it is thought to contribute over 90% of the membrane-associated PTP activity (1). Recognition of antigen by the T cell receptor (TCR) results in induction of a tyrosine phosphorylation cascade leading to T cell activation and is driven primarily by the activity of the Src family kinase (SFK), Lck (2). Counter-intuitively, CD45 is required for the efficient progression of this TCR-induced tyrosine phosphorylation signal, as it is required to dephosphorylate the negative regulatory site (Tyr-505) of Lck (reviewed in Refs. 3-5). This relieves inhibitory constraints on Lck and primes it for subsequent autophosphorylation at tyrosine 394 and activation. This activating function of CD45 and its requirement for efficient TCR signaling are well established. However, evidence from CD45 Ϫ/Ϫ thymocytes and certain CD45 Ϫ T cell lines indicates that the absence of CD45 can result in enhanced Lck phosphorylation at both the negative regulatory and autophosphorylation sites, suggesting a role for CD45 in both the activation and inactivation of Lck (4, 6, and reviewed in Ref. 7). Thus the function of CD45 may be to keep Lck under control, allowing activation, but preventing sustained activation or inactivation. It has been difficult to examine the role of CD45 in inactivati...

show abstract

Section: Discussioncontrasting

confidence: 39%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Although Expression Of Ptp␣ In a Cd45mentioning

confidence: 99%

Section: Cells-bw5147 Cd45mentioning

confidence: 99%

See 3 more Smart Citations

Differential Function of PTPα and PTPα Y789F in T Cells and Regulation of PTPα Phosphorylation at Tyr-789 by CD45

Maksumova

Wang

Wong

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Stanford

Svensson

Sacchetti

et al. 2016

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the joint extracellular matrix. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to RA FLS anomalous behavior. The receptor protein tyrosine phosphatase α (RPTPα), encoded by the PTPRA gene, is a key promoter of FAK signaling. Here we investigated whether RPTPα mediates FLS aggressiveness and RA pathogenesis. Methods Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, invasion and migration in transwell assays, survival by Annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in Ptpra−/− mice using the K/BxN serum transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone-marrow transplantation. Results RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumor necrosis factor and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of SRC on inhibitory Y527 and decreased phosphorylation of FAK on stimulatory Y397. Treatment of RA FLS with an inhibitor of FAK phenocopied knockdown of RPTPα. Ptpra-deficient mice were protected from arthritis development, which was due to radioresistant cells. Conclusions By regulating phosphorylation of SRC and FAK, RPTPα mediates pro-inflammatory and pro-invasive signaling in RA FLS, correlating with promotion of disease in an FLS-dependent model of RA.

show abstract

Association of PTPRT mutations with immune checkpoint inhibitors response and outcome in melanoma and non‐small cell lung cancer

Zhang

Shi

et al. 2021

Cancer Medicine

View full text Add to dashboard Cite

show abstract

Protein Tyrosine Phosphatase α Regulates Fyn Activity and Cbp/PAG Phosphorylation in Thymocyte Lipid Rafts

Cited by 46 publications

References 76 publications

Differential Function of PTPα and PTPα Y789F in T Cells and Regulation of PTPα Phosphorylation at Tyr-789 by CD45

Differential Function of PTPα and PTPα Y789F in T Cells and Regulation of PTPα Phosphorylation at Tyr-789 by CD45

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Association of PTPRT mutations with immune checkpoint inhibitors response and outcome in melanoma and non‐small cell lung cancer

Contact Info

Product

Resources

About