Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR.

Streuli, Michel; Krueger, Neil X.; Thai, Tran C.; Tang, May; Saito, Haruo

doi:10.1002/j.1460-2075.1990.tb07415.x

Cited by 346 publications

(248 citation statements)

References 39 publications

(18 reference statements)

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“…4). PTP activity assays that were done in parallel demonstrate that LAR-D1 is catalytically active and LAR-D2 is not (data not shown), consistent with previous reports (6). Taken together, the finding that the catalytically active PTP1B and LAR-D1 are readily oxidized indicates that there is not a strict inverse correlation between catalytic activity and oxidizability.…”

Section: Fig 1 Differential Oxidation Of Rptp␣-d1 and Rptp␣-d2supporting

confidence: 90%

Differential Oxidation of Protein-tyrosine Phosphatases

Groen

Lemeer

Wijk

et al. 2005

Journal of Biological Chemistry

121

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Oxidation is emerging as an important regulatory mechanism of protein-tyrosine phosphatases (PTPs).Here we report that PTPs are differentially oxidized, and we provide evidence for the underlying mechanism. The membrane-proximal RPTP␣-D1 was catalytically active but not readily oxidized as assessed by immunoprobing with an antibody that recognized oxidized catalytic site cysteines in PTPs (oxPTPs). In contrast, the membrane-distal RPTP␣-D2, a poor PTP, was readily oxidized. Oxidized catalytic site cysteines in PTP immunoprobing and mass spectrometry demonstrated that mutation of two residues in the Tyr(P) loop and the WPD loop that reverse catalytic activity of RPTP␣-D1 and RPTP␣-D2 also reversed oxidizability, suggesting that oxidizability and catalytic activity are coupled. However, catalytically active PTP1B and LAR-D1 were readily oxidized. Oxidizability was strongly dependent on pH, indicating that the microenvironment of the catalytic cysteine has an important role. Crystal structures of PTP domains demonstrated that the orientation of the absolutely conserved PTP loop arginine correlates with oxidizability of PTPs, and consistently, RPTP-D1, with a similar conformation as RPTP␣-D1, was not readily oxidized. In conclusion, PTPs are differentially oxidized at physiological pH and H 2 O 2 concentrations, and the PTP loop arginine is an important determinant for susceptibility to oxidation.

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Section: Fig 1 Differential Oxidation Of Rptp␣-d1 and Rptp␣-d2supporting

confidence: 90%

Differential Oxidation of Protein-tyrosine Phosphatases

Groen

Lemeer

Wijk

et al. 2005

Journal of Biological Chemistry

121

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“…Two amino acids within this region (cysteine and arginine in position 1 and 7 of C5XR-1, respectively) are not only conserved among members of the phosphotyrosine phosphatase gene family, but have also been shown necessary for both the biological function and tyrosine phosphatase activity of edc25 (Dunphy and Kumagai, 1991;Gautier et al, 1991;Millar et al, 1991), and for the activity of tyrosine phosphatases in general (Streuli et al, 1990;. It is believed that these amino acids are directly involved in binding and releasing of phosphate groups by tyrosine phosphatases (Streuli et al, 1990;. Consequently, we have based our choice of peptide on raising antisera that recognize this putative catalytic site on cdc25 proteins.…”

Section: Discussionmentioning

confidence: 99%

“…This sequence CEFSSKRGPDLLR (referred to as CSXR1) (Fig. 1 B) has been shown to belong to the phosphatase consensus site of cdc25 (Gautier et al, 1991;Millar et al, 1991); particularly, the motif C5XR is conserved throughout evolution and is also present in other protein phosphatases such as human T cell PTP or vaccinia virus PTP Streuli et al, 1990), and represents the catalytic site of the cdc25 phosphatase activity. The CSXR1 sequence is identical to the corresponding region of a starfish cdc25 protein that was determined by DNA sequence analysis of starfish cdc25 gene, cloned by PCR using degenerate primers as previously described (Sadhu et al, 1990).…”

Section: Expression Of Cdc25 Protein In Nontransformed Mammalian Fibrmentioning

confidence: 99%

cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells.

Girard¹,

Strausfeld²,

Cavadore³

et al. 1992

The Journal of Cell Biology

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Abstract. A family of proteins homologous to the cdc25 gene product of the fission yeast bear specific protein tyrosine phosphatase activity involved in the activation of the p34~a-cyclin B kinase. Using atfinitypurified antibodies raised against a synthetic peptide corresponding to the catalytic site of the cdc25 phosphatase, we show that cdc25 protein is constitutively expressed throughout the cell cycle of nontransformed mammalian fibroblasts and does not undergo major changes in protein level. By indirect immunofluorescence, cdc25 protein is found essentially localized in the nucleus throughout interphase and during early prophase. Just before the complete nuclear envelope breakdown at the prophase-prometaphase boundary, cdc25 proteins are redistributed throughout the cytoplasm. During metaphase and anaphase, cdc25 staining remains distributed throughout the cell and excludes the condensed chromosomes. The nuclear locale reappears during telophase. In light of the recent data describing the cytoplasmic localization of cyclin B protein (Pines, J., and T. Hunter. 1991. J. Cell Biol. 115:1-17), the data presented here suggest that separation in two distinct cellular compartments of the cdc25 phosphatase and its substrate p34~c2-cyclin B may be of importance in the regulation of the cdc2 kinase activity.

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“…The 150-kDa Esubunit is composed of three Ig domains and eight Fn III domains, whereas the 85-kDa P-subunit has a short extracellular domain, a transmembrane domain and two tandemly repeated PTPase domains, 1 and 2 (Streuli et al, 1992(Streuli et al, , 1998Tsujikawa et al, 2001). Previous investigations suggest that domain 2 is structurally very similar to domain 1 and that its function may be to regulate the catalytic activity or specificity of domain 1 Streuli et al, 1990;Wang and Pallen, 1991;Nam et al, 1999). LAR has been reported to play a regulatory role in insulin signalling via the extracellular and two PTPase domains of the P-subunit (Hashimoto et al, 1992;Zhang et al, 1994;Serra et al, 1995;Tsujikawa et al, 2001).…”

mentioning

confidence: 99%

Overexpression of leucocyte common antigen (LAR) P-subunit in thyroid carcinomas

et al. 2003

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Protein tyrosine phosphatase (PTPase) dephosphorylation and protein tyrosine kinase (PTKs) phosphorylation of key signal transduction proteins may be regulated by extracellular signals, making PTPases important in the regulation of cell proliferation. Leucocyte common antigen (LAR), a receptor-like PTPase, consists of E-subunit, containing the cell adhesion molecule-like receptor region, and P-subunit specific for a short segment of the extracellular region, the transmembrane peptide, and two cytoplasmic PTPase domains. We produced a monoclonal antibody against the LAR P-subunit for immunohistochemical screening of LAR expression in normal and tumourous tissues. Gliomas and gastric, colorectal, lung, breast and prostate cancers showed weak and relatively infrequent expression. Intense and diffuse expression, however, was detected in 95% (227 out of 239) of thyroid carcinomas, but only 12% (22 out of 128) of adenomas and no cases of benign thyroid disease were immunopositive. In contrast to broad staining in carcinomas, LAR expression in thyroid adenomas was often found in small focal or locally invasive areas. Western blot analysis similarly detected LAR P-subunit protein in thyroid carcinomas, but not in normal tissues. We believe this to be the first demonstration of LAR overexpression in thyroid carcinoma and may help to elucidate the role of PTPases in the development of malignancy.

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Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR.

Cited by 346 publications

References 39 publications

Differential Oxidation of Protein-tyrosine Phosphatases

Differential Oxidation of Protein-tyrosine Phosphatases

cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells.

Overexpression of leucocyte common antigen (LAR) P-subunit in thyroid carcinomas

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