Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine phosphorylation is a key regulator of cell growth regulation and, when aberrant, is linked with the process of oncogenic transformation. Since tyrosine phosphatases (PTP) reverse phosphorylation mediated by tyrosine kinases (PTK), it has been hypothesized, but insufficiently studied to date, that PTPs function as tumor suppressors. Alternatively, PTPs may augment signal transduction by repriming substrates. To begin to assess the role of PTPs in ovarian cancer cell growth regulation, PTP partial cDNAs were cloned from the OVCA 433 ovarian cancer cell line using RT/PCR and degenerate oligonucleotide primers for the PTP consensus domain. Thirteen partial cDNAs were isolated, the sequences of which, when compared to GenBank, suggested that they were derived from PTP family members. These included PTP-alpha, PTP-gamma, LAR, PTP-delta, T-cell PTP, PTP-2A(1D), PTP-1B, PTP-1C, PTP-H1, PTP-PEST, PTP-Gallus, and two isolates which potentially represent novel PTPs. Steady-state expression analyses revealed that PTP-1B expression was undetectable in normal epithelium but was expressed in four of five ovarian cancer cell lines. In contrast, the expression of two SH2-containing PTPs, PTP-1C and PTP-2A, was detected in the normal ovarian epithelium but lost from one or more ovarian cancer cell lines. Finally, PTP-1B, PTP-alpha, and PTP-H1 expression was increased following HER-2/neu transfection of ovarian cancer cell lines. These results suggest that both normal ovarian epithelial cells and ovarian cancer cells express multiple PTPs. Further, some PTPs are differentially expressed between normal ovarian epithelium and ovarian cancer cells. Intriguingly, the transfection and increased expression of the prognostically significant HER-2/neu PTK induced a selective increase in the expression of the PTP-alpha, PTP-1B, and PTP-H1 tyrosine phosphatases.
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PMID:Transfection of human ovarian cancer cells with the HER-2/neu receptor tyrosine kinase induces a selective increase in PTP-H1, PTP-1B, PTP-alpha expression. 862 39

The identification of substrates of protein tyrosine phosphatases (PTPs) is an essential step toward a complete understanding of the physiological function of members of this enzyme family. PTPs are defined by a conserved catalytic domain harboring 27 invariant residues. From a mutagenesis study of these invariant residues that was guided by our knowledge of the crystal structure of PTP1B, we have discovered a mutation of the invariant catalytic acid (Asp-181 in PTP1B) that converts an extremely active enzyme into a "substrate trap." Expression of this D181A mutant of PTP1B in COS and 293 cells results in an enzyme that competes with endogenous PTP1B for substrates and promotes the accumulation of phosphotyrosine primarily on the epidermal growth factor (EGF) receptor as well as on proteins of 120, 80, and 70 kDa. The association between the D181A mutant of PTP1B and these substrates was sufficiently stable to allow isolation of the complex by immunoprecipitation. As predicted for an interaction between the substrate-binding site of PTP1B and its substrates, the complex is disrupted by vanadate and, for the EGF receptor, the interaction absolutely requires receptor autophosphorylation. Furthermore, from immunofluorescence studies, the D181A mutant of PTP1B appeared to retain the endogenous EGF receptor in an intracellular complex. These results suggest that the EGF receptor is a bona fide substrate for PTP1B in vivo and that one important function of PTP1B is to prevent the inappropriate, ligand-independent, activation of newly synthesized EGF receptor in the endoplasmic reticulum. This essential catalytic aspartate residue is present in all PTPs and has structurally equivalent counterparts in the dual-specificity phosphatases and the low molecular weight PTPs. Therefore we anticipate that this method may be widely applicable to facilitate the identification of substrates of other members of this enzyme family.
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PMID:Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases. 905 Aug 38

We have synthesized a tris-sulfotyrosyl dodecapeptide (3S-peptide-I) that corresponds to the major autophosphorylation domain within the insulin receptor beta-subunit and showed that it potently inhibited insulin receptor dephosphorylation by protein tyrosine phosphatases (PTPases) in vitro. 3S-peptide-I also inhibited tyrosine dephosphorylation of a synthetic peptide by the recombinant PTPase PTP-1B, indicating that 3S-peptide-I interacts directly with PTPase, causing its inactivation. The peptide had no effect on the activity of serine/threonine phosphatases, PP-1 and PP-2A, or alkaline phosphatase. Furthermore, we found that the introduction of a N-stearyl derivative of 3S-peptide-I in CHO/HIRc cells caused a significant increase in insulin-stimulated phosphorylation of the insulin receptor. In contrast, ligand-stimulated phosphorylation of epidermal growth factor (EGF) receptor in CHO cells overexpressing EGF receptors was not affected by the presence of N-stearyl-3S-peptide-I. These data suggest that by inhibiting dephosphorylation of the insulin receptor in intact cells, 3S-peptide-I may specifically enhance insulin signalling.
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PMID:Specific inhibition of insulin receptor dephosphorylation by a synthetic dodecapeptide containing sulfotyrosyl residues as phosphotyrosyl mimetic. 934 28

Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.
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PMID:Regulation of ROS signal transduction by NADPH oxidase 4 localization. 1857 11