LowMrPhosphotyrosine Protein Phosphatase Interacts with the PDGF Receptor Directly via Its Catalytic Site

Chiarugi, Paola; Cirri, Paolo; Raugei, Giovanni; Manao, Giampaolo; Taddei, Letizia; Ramponi, Giampietro

doi:10.1006/bbrc.1996.0174

Cited by 43 publications

(30 citation statements)

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“…Binding of Afadin to SHP-2-PTPs that are known to interact with and dephosphorylate PDGF receptor include SHP-2, LMW-PTP, PTP-1B, PTP-PEST, and TC-PTP (26,27). Of these phosphatases, SHP-2 and LMW-PTP have been reported to be highly expressed in NIH3T3 cells (26,40).…”

Section: Prolongation Of the Pdgf-inducedmentioning

confidence: 99%

“…Of these phosphatases, SHP-2 and LMW-PTP have been reported to be highly expressed in NIH3T3 cells (26,40). We examined by the co-immunoprecipitation assay whether afadin associates with SHP-2 and/or LMW-PTP.…”

Section: Prolongation Of the Pdgf-inducedmentioning

confidence: 99%

“…Tyrosine-phosphorylated PDGF receptor is in turn dephosphorylated and inactivated by protein-tyrosine phosphatases (PTPs) such as Src homology 2 (SH2) domain-containing phosphatase-2 (SHP-2) (26,27). SHP-2 is a widely expressed cytosolic non-transmembrane PTP containing two SH2 domains at the N terminus and a single central phosphatase domain.…”

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confidence: 99%

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Regulation of Platelet-derived Growth Factor Receptor Activation by Afadin through SHP-2

Nakata

Fujita

Kitagawa

et al. 2007

Journal of Biological Chemistry

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Upon binding of platelet-derived growth factor (PDGF), PDGF receptor is autophosphorylated at tyrosine residues in its cytoplasmic region, which induces the activation of diverse intracellular signaling pathways such those involving Ras-ERK, c-Src, and Rap1-Rac. Signaling through activated Ras-ERK promotes cell cycle and cell proliferation. The sequential activation of Rap1 and Rac affects cellular morphology and induces the formation of leading-edge structures, including lamellipodia, peripheral ruffles, and focal complexes, resulting in the enhancement of cell movement. In addition to the promotion of cell proliferation, the Ras-ERK signaling is involved in the regulation of cellular morphology. Here, we showed a novel role of afadin in the regulation of PDGF-induced intracellular signaling and cellular morphology in NIH3T3 cells. Afadin was originally identified as an actin filament-binding protein, which binds to a cell-cell adhesion molecule nectin and is involved in the formation of cell-cell junctions. When afadin was tyrosine-phosphorylated by c-Src activated in response to PDGF, afadin physically interacted with and increased the phosphatase activity of Src homology 2 domain-containing phosphatase-2 (SHP-2), a protein-tyrosine phosphatase that dephosphorylates PDGF receptor, leading to the prevention of hyperactivation of PDGF receptor and the Ras-ERK signaling. In contrast, knockdown of afadin or SHP-2 induced the hyperactivation of PDGF receptor and Ras-ERK signaling and consequently suppressed the formation of leading-edge structures. Thus, afadin plays a critical role in the proper regulation of the PDGF-induced activation of PDGF receptor and signaling by Ras-ERK. This effect, which is mediated by SHP-2, impacts cellular morphology.Afadin is a nectin-and actin filament (F-actin) 2 -binding protein that connects nectin to the actin cytoskeleton (1). Nectin is a Ca 2ϩ -independent immunoglobulin-like molecule that first forms cell-cell adhesion and then assembles cadherin at the nectin-based cell-cell adhesion sites, resulting in the formation of adherens junctions (AJs) in epithelial cells and fibroblasts (2, 3). The nectin family of proteins comprises four members, nectin-1, -2, -3, and -4. A series of our studies revealed the roles and modes of action of nectin and afadin for the formation of AJs (2-10). Nectin initiates the formation of cell-cell adhesion and then induces the activation of Rap1, Cdc42, and Rac small G proteins through the activation of c-Src. Subsequently, Cdc42 and Rac bind to IQGAP1 and induce the reorganization of the actin cytoskeleton, thereby causing the accumulation of nontrans-interacting E-cadherin at the nectin-based cell-cell adhesion sites. On the other hand, afadin, which binds to Rap1 activated by the action of nectin, associates with p120 ctn and inhibits the endocytosis of accumulated non-trans-interacting E-cadherin to facilitate the trans-interaction of E-cadherin. In parallel with these processes, Cdc42 increases the number of filopodia and cell-cell contact si...

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Section: Prolongation Of the Pdgf-inducedmentioning

confidence: 99%

Section: Prolongation Of the Pdgf-inducedmentioning

confidence: 99%

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Regulation of Platelet-derived Growth Factor Receptor Activation by Afadin through SHP-2

Nakata

Fujita

Kitagawa

et al. 2007

Journal of Biological Chemistry

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“…In vertebrates, LMWPTPs participate in the complex signaling cascades originating from the stimulation of some growth factor receptors by their respective speci c factors. In particular, we have demonstrated that the enzyme is able to bind and dephosphorylate PDGF and insulin receptors only when they are activated, thereby downregulating them (6,8,18,19). In addition, the transfection of the active enzyme and of its negative-dominant form (the mutant C12S, which is able to bind substrates but is catalytically inactive) in NIH/3T3 broblasts demonstrated that, whereas the growth rate of these cells is decreased by overexpression of the active enzyme, it is increased by the overexpression of the negative-dominant form (18).…”

Section: Discussionmentioning

confidence: 99%

Thiolation of Low-Mr Phosphotyrosine Protein Phosphatase by Thiol-Disulfides

Degl’Innocenti¹,

Caselli²,

Rosati³

et al. 1999

IUBMB: Life

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SummaryThiol-disul des cause a time-and a concentration-dependent inactivation of the low-M r phosphotyrosine protein phosphatase (PTP). We demonstrated that six of eight enzyme cysteines have similar reactivity against 5,5 0 -dithiobis(nitrobenzoic acid): Their thiolation is accompanied by enzyme inactivation. The inactivation of the enzyme by glutathione disul de also is accompanied by the thiolation of six cysteine residues. Inorganic phosphate, a competitive enzyme inhibitor, protects the enzyme from inactivation, indicating that the inactivation results from thiolation of the essential active-site cysteine of the enzyme. The inactivation is reversed by dithiothreitol. Although all PTPs have three-dimensional active-site structures very similar to each other and also have identical reaction mechanisms, the thiol group contained in the active site of low-M r PTP seems to have lower reactivity than that of other PTPs in the protein thiolation reaction. IUBMB Life, 48: 505-511, 1999

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“…Acid phosphatase (ACP1) is a tyrosine phosphatase protein, and is affected by reactive oxygen species. It has a role as fl avin mononucleotide (FMN) phosphatase and subsequently interferes with glutathione reductase activity (Chiarugi, et al, 1996;Fuchs, Shekels & Bernlohr, 1992;Gerli, et al, 1990;Magenis, et al, 1975;Mohreweiser & Novotny, 1982).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in Portuguese children with Down syndrome

Pinto¹,

Neves²,

Palha³

et al. 2002

Downs Syndr. Res. Pract.

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-Background -Individuals with Down syndrome have an accelerated process of ageing which is thought to be associated with oxidative stress. Aim -Since Zn/Cu superoxide dismutase is increased by about 50% in children with Down syndrome, glutathione and other less known antioxidant mechanisms were studied to determine whether there were changes in reactive oxygen species. Methods -Plasma reduced and oxidised glutathione and red blood cells enzymes including acid phosphatase, methemoglobin reductase and transmembrane reductase were evaluated in Portuguese children with Down syndrome and their siblings, who were used as a control group. Results -No significant differences were found between the study and control groups. A negative correlation was noted between total glutathione and acid phosphatase in the siblings without Down syndrome, but not in the children with Down syndrome. Conclusion -Although it is claimed that the production of hydrogen peroxide is enhanced in children with Down syndrome, their antioxidant mechanisms do not seem to be significantly different compared with their siblings. This may result in an excess of reactive oxygen species that could help to explain accelerated ageing in children with Down syndrome. Further studies will be needed to shed light on these mechanisms.

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LowMrPhosphotyrosine Protein Phosphatase Interacts with the PDGF Receptor Directly via Its Catalytic Site

Cited by 43 publications

References 0 publications

Regulation of Platelet-derived Growth Factor Receptor Activation by Afadin through SHP-2

Regulation of Platelet-derived Growth Factor Receptor Activation by Afadin through SHP-2

Thiolation of Low-Mr Phosphotyrosine Protein Phosphatase by Thiol-Disulfides

Oxidative stress in Portuguese children with Down syndrome

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