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At least 919 records · Page 51Linked to original sources
PubMed1997

Short-term effect of parathyroidectomy on biochemical markers in primary and secondary hyperparathyroidism.

This study has been carried out in order to evaluate several bone metabolic markers after parathyroidectomy in patients with primary hyperparathyroidism (PHP) and secondary hyperparathyroidism (SHP). The subjects studied were 6 patients with PHP (5 females, 1 male, aged 64-83 years) and 5 patients with SHP on chronic maintenance hemodialysis with skeletal symptoms (2 females, 3 males, aged 57-67 years). In PHP, serum alkaline phosphatase (ALP) and procollagen type I carboxy-terminal propeptides (PICP) levels showed a trend to increase gradually after parathyroidectomy, changes which were statistically significant (ALP, p = 0.0375; PICP, p = 0.0006). The serum bone Gla protein (BGP) level showed no significant change throughout the pre- and postoperative periods (p = 0.7512). Urinary pyridinoline (Pyr.) and deoxypyridinoline (DPyr.) levels showed rapid decreases after parathyroidectomy (Pyr.; p = 0.0014, DPyr., p = 0.0087). In SHP, individual values of serum ALP in 3 patients with complete parathyroid resection and 1 patient with incomplete parathyroid resection showed a tendency to increase. Individual values of serum BGP and PICP increased after parathyroidectomy in 3 patients with complete parathyroid resection but not in the 2 patients with incomplete parathyroid resection. Individual values of the serum carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) level showed no certain trend. The results obtained after surgery indicate that there is a positive uncoupling of the two processes of bone remodeling, and serum PICP and urinary pyridinium cross-links are good specific markers for the evaluation of potential recovery of bone damage after parathyroidectomy.

Aged↗
PubMed1998

Superclustering of B cell receptor and Fc gamma RIIB1 activates Src homology 2-containing protein tyrosine phosphatase-1.

Fc gamma RIIB1 (CD32) is a receptor that binds the Fc domain of Ag-complexed IgG. Coaggregation of B cell receptor (BCR) and Fc gamma RIIB1 generates a dominant negative signal that inhibits B cell activation. In Ag-specific Id-positive B cells, the co-cross-linking of BCR and Fc gamma RIIB1 by anti-Id Ab resulted in the association of both Src homology 2-containing protein tyrosine phosphatase (SHP-1) and Src homology 2-containing inositol phosphatase (SHIP) with the Fc gamma RIIB1; however, only SHIP activity was detected. "Superclustering" of the BCR and Fc gamma RIIB1 complex induced by stimulation with anti-Id Ab plus polyvalent Ag synergistically activated SHP-1. The degree of co-cross-linking between BCR and Fc gamma RIIB1 may determine the activation status of SHP-1 and SHIP.

Animals↗
PubMed1999

Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed on activated T cells that can inhibit T cell responses induced by activation of the TCR and CD28. Studies with phosphorylated peptides based on the CTLA-4 intracellular domain have suggested that tyrosine phosphorylation of CTLA-4 may regulate its interactions with cytoplasmic proteins that could determine its intracellular trafficking and/or signal transduction. However, the kinase(s) that phosphorylate CTLA-4 remain uncharacterized. In this report, we show that CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218. A similar pattern of tyrosine phosphorylation was found in pervanadate-treated Jurkat T cells stably expressing CTLA-4. Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. CTLA-4 phosphorylation induced the association of CTLA-4 with the tyrosine phosphatase SHP-2, but not with phosphatidylinositol 3-kinase. In contrast, Lck-induced phosphorylation of CD28 resulted in the recruitment of phosphatidylinositol 3-kinase, but not SHP-2. These findings suggest that phosphorylation of CD28 and CTLA-4 by Lck activates distinct intracellular signaling pathways. The association of CTLA-4 with Src kinases and with SHP-2 results in the formation of a CTLA-4 complex with the potential to regulate T cell activation.

Abatacept↗
PubMed1998

Cloning of two members of the SIRP alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells.

Recent experimental studies have greatly clarified the function of cell surface molecules in the induction and modulation of T cell responses by antigen-presenting cells (APC). However, the differences in ability to stimulate T cells evident for different types and subpopulations of the same APC, such as dendritic cell subsets, is less well understood. This report details an investigation of an antigen expressed on monocytes that is also expressed on a subset of cattle afferent lymph veiled cells (ALVC). A cDNA library derived from cattle monocytes was screened with monoclonal antibodies (mAb) for expression in COS-7 cells. Using separate mAb for screening, two cDNA were cloned, the sequences of which showed a single long open reading frame encoding a predicted type I glycoprotein of 506 amino acids that contained three immunoglobulin superfamily domains and a long 112-amino acid cytoplasmic tail. We have termed this antigen MyD-1, reflecting its myeloid and dendritic cell distribution. Analysis of the EMBL database revealed that the molecule is a member of the recently described family of signal regulatory proteins (SIRP). The outeremost Ig domain was of the adhesion/receptor I-type, suggesting that MyD-1 might bind to a ligand on another cell. Evidence for this was subsequently obtained by demonstrating that COS-7 cells transfected with MyD-1 cDNA bound CD4 T cells and this binding was blocked by specific mAb. The potential importance of this interaction was supported by the finding that the proliferation of resting memory CD4 T cells to ovalbumin-pulsed monocytes was significantly reduced in the presence of mAb to MyD-1. A role for the molecule in the modulation of the monocyte/dendritic APC response is also predicted from the existence of multiple potential tyrosine phosphorylation sites in the cytoplasmic domain, including the presence of an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the observation that the SIRP alpha family members have been shown to bind to SHP-1 and SHP-2. Together these data indicate a possible functional importance for MyD-1 in the regulation of monocyte and dendritic cell function.

Amino Acid Sequence↗
PubMed1999

Molecular and functional characterization of IRp60, a member of the immunoglobulin superfamily that functions as an inhibitory receptor in human NK cells.

In this study we describe the functional and molecular characterization of IRp60 (inhibitory receptor protein 60), an inhibitory receptor expressed on all human NK cells. The IRp60 molecule has been identified by the generation of three novel monoclonal antibodies (mAb). Cross-linking of IRp60 by specific mAb strongly inhibits the spontaneous cytotoxicity of NK cells as well as the NK-mediated cytolytic activity induced via different non-HLA-specific or HLA-specific activating receptors. IRp60 is a 60-kDa glycoprotein that, upon sodium pervanadate treatment, becomes tyrosine phosphorylated and associates with the SH2-containing phosphatases SHP-1 and SHP-2. The IRp60 gene is located on human chromosome 17 and encodes a molecule belonging to the immunoglobulin (Ig) superfamily characterized by a single V-type Ig-like domain in the extracellular portion. The cytoplasmic tail contains three classical immunoreceptor tyrosine-based inhibitory motifs. Southern blot analysis revealed cross-hybridization with monkey and mouse genomic DNA, thus suggesting that IRp60 may be conserved among different species. Moreover, based on the use of different anti-IRp60 mAb, we could identify two IRp60 allelic variants. Since IRp60 is also expressed by other cell types, including T cell subsets, monocytes and granulocytes, it may play a more general role in the negative regulation of different leukocyte populations.

Amino Acid Sequence↗
PubMed2000

CD47 is a ligand for rat macrophage membrane signal regulatory protein SIRP (OX41) and human SIRPalpha 1.

The rat OX41 antigen is a cell surface protein containing three immunoglobulin superfamily domains and intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIM). It is a homologue of the human signal-regulatory protein (SIRP) also known as SHPS-1, BIT or MFR. Cell activation-induced phosphorylation of the intracellular ITIM motifs induces association with the tyrosine phosphatases SHP-1 and SHP-2. To identify the physiological OX41 ligand, recombinant OX41-CD4d3+4 fusion protein was coupled to fluorescent beads to produce a multivalent cell binding reagent. The OX41-CD4d3+4 beads bound to thymocytes and concanavalin A-stimulated splenocytes. This interaction was blocked by the monoclonal antibody (mAb) OX101. Affinity chromatography with OX101 mAb and peptide sequencing revealed the rat SIRP ligand to be CD47 (integrin-associated protein). A direct interaction between human SIRP and human CD47 was demonstrated using purified recombinant proteins and surface plasmon resonance ruling out the involvement of other proteins known to be associated with CD47. The affinity of the SIRP/CD47 interaction was K(d) approximately 8 microM at 37 degrees C with a k(off )>/=2.1 s(-1). The membrane-distal SIRP V-like domain was sufficient for binding to CD47.

Animals↗
PubMed2000

Association of signal-regulatory proteins beta with KARAP/DAP-12.

The signal-regulatory proteins (SIRP) are Ig-like cell surface receptors detected in hematopoietic and non-hematopoietic cells. SIRP are classified as SIRPalpha molecules, containing a 110- to 113-amino acid long, or SIRPbeta molecules, with a 5-amino acid long intracytoplasmic domain. SIRPalpha molecules belong to inhibitory immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing molecules. The majority of ITIM-bearing receptors are paired with activating isoforms, which share highly related extracytoplasmic domains but harbor a shorter cytoplasmic domain devoid of ITIM and contain a charged amino acid residue in their transmembrane domain. Activating receptors are associated with immunoreceptor tyrosine-based activation motif (ITAM)-bearing proteins, such as KARAP/DAP-12 and FcRgamma. In this report, we show that human SIRPbeta1 is included in an oligomeric complex with KARAP/DAP-12 in hematopoietic and non-hematopoietic transfectant cells as well as in human monocytes. The physical association between SIRPbeta1 and KARAP/DAP-12 results in the functional coupling of SIRPbeta1 engagement to the recruitment of the protein tyrosine kinase Syk and to serotonin release in RBL cell transfectants. Therefore our results show that SIRPbeta1 acts as an activating isoform of SIRPalpha molecules, confirming the co-existence of inhibitory ITIM-bearing molecules, recruiting SHP-1 and SHP-2 protein tyrosine phosphatases, and activating counterparts, whose engagement couples to protein tyrosine kinases via ITAM-bearing molecules.

Adaptor Proteins, Signal Transducing↗
PubMed2001

A regulatory role for cytoplasmic YVKM motif in CTLA-4 inhibition of TCR signaling.

CTLA-4 negatively regulates TCR signaling, although the molecular basis for this effect has yet to be elucidated. The cytoplasmic YVKM motif, while binding to phosphatidylinositol 3-kinase, SHP-2 and the AP-1/AP-2 clathrin adaptor complexes, has been reported to play no role in CTLA-4 function. In contrast, in this study, we demonstrate that, although not essential, the YVKM motif contributes to optimal CTLA-4 blockage of TCRzeta or combined TCRzeta/CD28 signaling. Significantly, dependency on the YVKM motif varied with the mode of anti-receptor presentation, where soluble antibody ligation was more dependent on the presence of the motif than immobilized antibody. Previous studies have mainly relied on the use of immobilized antibody. Neither SHP-2 binding, alterations in TCRzeta chain phosphorylation, nor ZAP-70 recruitment was involved in CTLA-4 wild-type or mutant inhibition. Overall, our findings clearly implicate the YVKM motif in optimal CTLA-4 function.

Abatacept↗
PubMed1982

Schönlein-Henoch syndrome in patients with familial Mediterranean fever.

Ten episodes of Schönlein-Henoch purpura (SHP) in 8 patients with familial Mediterranean fever (FMF) were observed. Five episodes developed 3-14 days after penicillin injections, suggesting an etiologic association. FMF and SHP have clear clinical similarities, and if the frequency of association of the 2 diseases is indeed high, perhaps a common etiologic factor should be sought. An immune complex mechanism might be the link between these 2 disease entities.

Adolescent↗
PubMed1997

The role of phosphotyrosine phosphatases in haematopoietic cell signal transduction.

Phosphotyrosine phosphatases (PTPases) are the enzymes which remove phosphate groups from protein tyrosine residues. An enormous number of phosphatases have been cloned and sequenced during the past decade, many of which are expressed in haematopoietic cells. This review focuses on the biochemistry and cell biology of three phosphatases, the transmembrane CD45 and the cytosolic SH2-domain-containing PTPases SHP-1 and SHP-2, to illustrate the diverse ways in which PTPases regulate receptor signal transduction. The involvement of these and other PTPases has been demonstrated in haematopoietic cell development, apoptosis, activation and nonresponsiveness. A common theme in the actions of many haematopoietic cell PTPases is the way in which they modulate the thresholds for receptor signalling, thereby regulating critical events in the positive and negative selection of lymphocytes. There is growing interest in haematopoietic PTPases and their associated regulatory proteins as targets for pharmaceutical intervention and in the involvement of these enzymes in human disease.

Animals↗
PubMed2004

IREM-1 is a novel inhibitory receptor expressed by myeloid cells.

Using a three-hybrid strategy, we have identified a novel cell surface molecule which interacts with the Src homology 2 (SH2) domains of SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1), termed "immune receptor expressed on myeloid cells 1" (IREM-1). The full-length cDNA coding for a polypeptide of 290 amino acids presents an extracellular single V-type Ig domain, a transmembrane region and a cytoplasmic tail with five tyrosine residues, two of which are in the context of an immunoreceptor tyrosine-based inhibitory motif. Moreover, cDNA encoding for three other splicing forms of IREM-1, named IREM-1 splice variant (Sv)1, Sv2 and Sv3 were cloned by reverse transcription (RT)-PCR. The gene encoding for IREM-1 contains nine exons, is located on human chromosome 17 (17q25.1) and is homologous to previously identified molecules termed CMRF-35 and IRp60. RT-PCR, northern blot and FACS analysis with specific monoclonal antibodies indicated that IREM-1 is expressed on monocytes, granulocytes, and myeloid leukemia cell lines. Western blot analysis confirmed the recruitment of SHP-1 to IREM-1 and demonstrated that phosphotyrosine residue 205 is the main docking site for this interaction. Finally, cross-linking of IREM-1 results in the inhibition of FcRepsilon-induced activation. Our results indicate that IREM-1 is a novel inhibitory receptor of the Ig superfamily in myeloid cells.

Amino Acid Sequence↗
PubMed2005

Dual regulation of BCR-mediated growth inhibition signaling by CD72.

CD72 has been reported to regulate BCR-mediated signals both positively and negatively. SHP-1 and Grb2 bind, respectively, to ITIM1 and ITIM2 of CD72. We generated transformed B cell lines with an immature phenotype following J2 virus infection of splenocytes from CD72(-/-) and wild-type (Wt) mice. The transformed lines were infected with retroviral vectors carrying Tyr (Y) to Phe (F) substitutions in the ITIM sequences (ITIM1 mutated: Y7/F; ITIM2 mutated: Y39/F; and both ITIM mutated: Y7,39/F). Cross-linking of the BCR induced growth inhibition in transfectants expressing Wt CD72, but this response was less sensitive in transfectants with Y7,39/F. The Y7/F transfectants demonstrated the least sensitive response. We were not able to obtain transfectants with Y39/F, suggesting that CD72 associated with SHP-1, but not with Grb2, delivers a strong negative signal. Pre-ligation of CD72, which induces dephosphorylation of the molecule, partially rescued the Wt transfectants from growth inhibition, leading to a growth response profile similar to that of Y7,39/F transfectants. These results suggest that ITIM1/SHP-1 delivers a very strong negative signal that is down-modulated by signals through ITIM2/Grb2, leading to delivery of an attenuated negative signal. Thus, pre-ligation of CD72 results in the manifestation of an ostensible positive signal.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Negative regulation of hepatocellular carcinoma cell growth by signal regulatory protein alpha1.

Signal regulatory protein (SIRP) alpha1 is a member of the SIRP family that undergoes tyrosine phosphorylation and binds SHP-2 tyrosine phosphatase in response to various mitogens. The expression levels of SIRPalpha1 were decreased in HCC tissues, compared with the matched normal tissues. Exogenous expression of wild type SIRPalpha1, but not of a mutant SIRPalpha1 lacking the tyrosine phosphorylation sites, in SIRPalpha1-negative Huh7 human HCC cells resulted in suppression of tumor cell growth both in vitro and in vivo. Treatment of Huh7 transfectants with EGF or HGF induced tyrosine phosphorylation of SIRPalpha1 and its association with SHP-2, which were accompanied by reduced ERK1 activation. Expression of SIRPalpha1 significantly suppressed activation of NF-kappaB and also sensitized Huh7 cells to TNFalpha or cisplatin-induced cell death. In addition, SIRPalpha1-transfected Huh7 cells displayed reduced cell migration and cell spreading in a fashion that was dependent on SIRPalpha1/SHP-2 complex formation. In conclusion, a negative regulatory effect of SIRPalpha1 on hepatocarcinogenesis is exerted, at least in part, through inhibition of ERK and NF-kappaB pathways.

Antigens, Differentiation↗
PubMed2005

Cytokine-independent repression of rodent Ntcp in obstructive cholestasis.

Cholestatic liver injury is associated not only with accumulation of bile acids but also with activation of proinflammatory cytokines. Common bile duct ligation (CBDL) induces sustained downregulation of the Na(+)/taurocholate cotransporter (Ntcp) in rodent liver. Although repression of Ntcp during endotoxemia is cytokine mediated, it is unclear whether inflammatory cytokines contribute to this downregulation in obstructive cholestasis. Cytokine inactivation in CBDL rats and mice was either performed directly with tumor necrosis factor alpha (etanercept) or interleukin 1 beta inactivation (anakinra/AMG 719) or indirectly Kupffer cell depletion via intraperitoneal administration of liposome-encapsulated dichloromethylene bisphosphonate. Protein and messenger RNA (mRNA) expression of Ntcp and short heterodimer partner (SHP) were analyzed via Western and Northern blotting. Key regulators of Ntcp (hepatocyte nuclear factor 1 alpha [HNF-1alpha], HNF-4alpha, retinoid X receptor alpha [RXRalpha]:retinoic acid receptor alpha [RARalpha]) were studied via electrophoretic mobility shift analysis and nuclear Western blot analysis. Both methods of cytokine inactivation failed to maintain Ntcp protein or mRNA expression within 3 days after CBDL in either rats or mice (20%-40% of sham controls), while SHP mRNA expression increased three- to five-fold. Decreased nuclear HNF-1alpha and HNF-4alpha protein levels (45% and 60% of sham controls, respectively) and HNF-1alpha binding activity (32% of sham controls) were not restored during cytokine inactivation after CBDL, indicating cytokine-independent mechanisms of Ntcp regulation. RXRalpha:RARalpha binding remained unchanged in all experimental conditions. In conclusion, during obstructive cholestasis accumulating bile acids per se, without major contribution of cytokines, leads to downregulation of Ntcp via repression of HNF-1alpha and HNF-4alpha.

Animals↗
PubMed2006

Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis.

Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.

Adenocarcinoma↗
PubMedDate not supplied

Yeast Derlin Dfm1 interacts with Cdc48 and functions in ER homeostasis.

Recent studies have identified Derlin-1, a protein that associates with the AAA-ATPase p97 and is implicated in late steps in ER-associated protein degradation (ERAD). Derlin-1 has two Saccharomyces cerevisiae homologues, Der1p and Dfm1p. While Der1p has been studied extensively, little is known about Dfm1p. Accordingly, we investigated the role of Dfm1p in ERAD, ER homeostasis and interactions with the yeast p97 homologue Cdc48p. Dfm1p was not involved in the degradation of a number of Der1-dependent or -independent ERAD substrates, neither was it redundant with either Der1p or Sec61p in ERAD. However, Dfm1p had a role in ER homeostasis, since Dfm1p loss or overexpression could stimulate the unfolded protein response (UPR). Furthermore, Dfm1p interacted both genetically and physically with Cdc48p, the yeast p97 homologue, and this interaction required an eight amino acid sequence found in the C-terminus of Dfm1p that we have termed the SHP box. Our genetic studies are consistent with the lack of a role for Dfm1p in ERAD, but indicate it participates in ER-related Cdc48p actions distinct from retrotranslocation. Finally, sequence analysis indicated that the UPR-related and Cdc48p interaction functions of Dfm1p could be separated, implying this protein probably has numerous actions in the cell. Thus, the interaction between Derlins and p97 is conserved between yeast and mammals, although its function in ERAD is not. Furthermore, Dfm1p interacts with Cdc48p through its SHP boxes, and so defines a new motif for interaction with this widely-employed AAA-ATPase.

Adenosine Triphosphatases↗
PubMed2002

Regulation of postaggregation events induced by protease-activated receptor 1 ligation in human platelets: evidence of differential signaling pathways.

In a physiological milieu platelets continue to be exposed to agonists long after clot formation. We studied the regulation of postaggregation events consequent on protease-activated receptor (PAR) 1 ligation with either thrombin or the thrombin receptor-activating peptide (TRAP). Stimulation with TRAP (20 microM) but not with thrombin (1 U/ml) for 15 min evoked platelet disaggregation by about 30% and downregulation of high-affinity fibrinogen binding sites on integrin alpha(IIb)beta(3) to nearly prestimulation levels. Concurrently, only TRAP disorganized the actin-based cytoskeleton, with decrease in the cytoskeletal content of focal contact-associated proteins like integrin alpha(IIb)beta(3), Src, and focal adhesion kinase (FAK). While protein tyrosine kinases were activated during the initial period of platelet aggregation with either agonist, stimulation of protein tyrosine phosphatases determined the successive phase of reduced phosphotyrosine content. SHP-1, an abundant protein tyrosine phosphatase in the platelets, was tyrosine phosphorylated on challenge of PAR-1 and coprecipitated with two unidentified tyrosine phosphorylated proteins of 140 and 60 kDa; in addition, SHP-1 tyrosine phosphorylation (which is associated with enhanced phosphatase activity) was sustained until 15 min. Activity of calpain was upregulated following incubation with thrombin and not with TRAP. Collectively, these data suggest that signaling pathways elicited by PAR-1 agonists thrombin and TRAP are markedly different, which could have important implications on late platelet responses.

Blood Platelets↗
PubMed1994

Suicide inactivation of human prostatic acid phosphatase and a phosphotyrosine phosphatase.

4-Difluoromethylphenyl bis(cyclohexylammonium) phosphate was synthesized in 4 steps starting from dibenzyl phosphite and shown to be a time-dependent suicide inactivator of human prostatic acid phosphatase and the SHP protein tyrosine phosphatase. The inactivation of human prostatic acid phosphatase followed pseudo-first-order kinetics with inactivation constants of Ki = 1.0 mM; ki = 0.15 min-1 (t1/2 = 4.6 min at saturation). Phenyl phosphate protected the enzyme against inactivation, indicating that inactivation occurs in the active site. The inactivation of SHP also followed pseudo-first-order kinetics, with a t1/2 = approximately 15 min in the presence of 8.2 mM inhibitor. The mechanism of inactivation likely involves the enzymatic release of difluoromethyl phenol which rapidly eliminates fluoride, generating a quinone methide. This potent electrophile then reacts with residues at the active site of the enzyme. This inhibitor and peptidic derivatives thereof have excellent potential for selective inactivation and labeling of protein tyrosine phosphatases.

Acid Phosphatase↗