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At least 361 records · Page 20Linked to original sources
PubMed2002

Autocrine regulation of human prostate carcinoma cell proliferation by somatostatin through the modulation of the SH2 domain containing protein tyrosine phosphatase (SHP)-1.

The present study was intended to gain additional information on the growth regulation of prostate by somatostatin (SRIF) and the intracellular events involved. The human prostate adenocarcinoma cell lines PC-3 and LNCaP produce SRIF and express subtypes 2 and 5 of SRIF receptors. The secretion of SRIF is related to the proliferative status of these cells; an inverse relationship exists between cell proliferation and the amount of secreted SRIF. Moreover, the growth of PC-3 cells is inhibited by SRIF overexpression and increased by blockage of endogenous SRIF. Coincident with the increase in SRIF secretion, the activity and levels of the SH2 domain containing protein tyrosine phosphatase (SHP)-1, present in PC-3 cells are augmented, but the effect can be partially prevented by neutralization of secreted endogenously SRIF. The activity of SHP-1 is also stimulated by the SRIF analog RC160. Overexpression of SHP-1 induces inhibition of PC-3 cell growth. SHP-1 is also present in normal prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and well differentiated adenocarcinoma. In contrast, no signal is detected in poorly differentiated prostate cancer. These findings demonstrate that SRIF inhibits PC-3 and LNCaP cell proliferation through an autocrine/paracrine SRIF loop. This effect could be mediated by activation of the tyrosine phosphatase SHP-1 detected in these cells as well as in human prostate and prostate cancer.

Autocrine Communication↗
PubMed1999

Increased migration of the SHP prosthesis: radiostereometric comparison with the Lubinus SP2 design in 40 cases.

40 patients with primary arthrosis were randomized to receive either a cemented SHP (Scientific Hip Prosthesis) or Lubinus SP2 prosthesis. At 2 years radiostereometric measurements showed increased proximal migration (0.4/0.2 mm; p = 0.02) and more proximal wear (0.3/0.1 mm, p = 0.01) of the SHP socket. The SHP stem also subsided (-O.6/-0.1 mm, p<0.001) and rotated more into retroversion (2.6/0.3 degrees ) than did the SP2 design. This subsidence mainly occurred inside the cement mantle in 17 of 18 cases (13 SHP, 4 SP2), where this type of motion could be measured. The changes in bone mineral density evaluated with DEXA and the clinical results did not differ between the 2 groups. The subsidence of the SHP stem is the most pronounced so far recorded with radiostereometry in stems without a completely polished surface. This subsidence and the rotational instability imply a substantial risk of abrasive wear and increased stresses in the cement mantle.

Aged↗
PubMed2001

Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation.

To study the mechanism by which protein tyrosine phosphatases (PTPs) regulate CD3-induced tyrosine phosphorylation, we investigated the distribution of PTPs in subdomains of plasma membrane. We report here that the bulk PTP activity associated with T cell membrane is present outside the lipid rafts, as determined by sucrose density gradient sedimentation. In Jurkat T cells, approximately 5--10% of Src homology 2 domain-containing tyrosine phosphatase (SHP-1) is constitutively associated with plasma membrane, and nearly 50% of SHP-2 is translocated to plasma membrane after vanadate treatment. Similar to transmembrane PTP, CD45, the membrane-associated populations of SHP-1 and SHP-2 are essentially excluded from lipid rafts, where other signaling molecules such as Lck, linker for activation of T cells, and CD3 zeta are enriched. We further demonstrated that CD3-induced tyrosine phosphorylation of these substrates is largely restricted to lipid rafts, unless PTPs are inhibited. It suggests that a restricted partition of PTPs among membrane subdomains may regulate protein tyrosine phosphorylation in T cell membrane. To test this hypothesis, we targeted SHP-1 into lipid rafts by using the N-terminal region of Lck (residues 1--14). The results indicate that the expression of Lck/SHP-1 chimera inside lipid rafts profoundly inhibits CD3-induced tyrosine phosphorylation of CD3 zeta/epsilon, IL-2 generation, and nuclear mobilization of NF-AT. Collectively, these results suggest that the exclusion of PTPs from lipid rafts may be a mechanism that potentiates TCR/CD3 activation.

CD3 Complex↗
PubMed2004

Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation.

IL-2 stimulation of T lymphocytes induces the tyrosine phosphorylation and adaptor function of the insulin receptor substrate/Grb2-associated binder (Gab) family member, Gab2. In addition, Gab2 undergoes a marked decrease in its mobility in SDS-PAGE, characteristic of migration shifts induced by serine/threonine phosphorylations in many proteins. This migration shift was strongly diminished by treating cells with the MEK inhibitor U0126, indicating a possible role for ERK in Gab2 phosphorylation. Indeed, ERK phosphorylated Gab2 on a consensus phosphorylation site at serine 623, a residue located between tyrosine 614 and tyrosine 643 that are responsible for Gab2/Src homology 2 domain-containing tyrosine phosphatase (SHP)-2 interaction. We report that pretreatment of Kit 225 cells with U0126 increased Gab2/SHP-2 association and tyrosine phosphorylation of SHP-2 in response to IL-2, suggesting that ERK phosphorylation of serine 623 regulates the interaction between Gab2 and SHP-2, and consequently the activity of SHP-2. This hypothesis was confirmed by biochemical analysis of cells expressing Gab2 WT, Gab2 serine 623A or Gab2 tyrosine 614F, a mutant that cannot interact with SHP-2 in response to IL-2. Activation of the ERK pathway was indeed blocked by Gab2 tyrosine 614F and slightly increased by Gab2 serine 623A. In contrast, STAT5 activation was strongly enhanced by Gab2 tyrosine 614F, slightly reduced by Gab2 WT and strongly inhibited by Gab2 serine 623A. Analysis of the rate of proliferation of cells expressing these mutants of Gab2 demonstrated that tyrosine 614F mutation enhanced proliferation whereas serine 623A diminished it. These results demonstrate that ERK-mediated phosphorylation of Gab2 serine 623 is involved in fine tuning the proliferative response of T lymphocytes to IL-2.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Tyrosine phosphatase SHP-1 immunoreactivity increases in a subset of astrocytes following deafferentation of the chicken auditory brainstem.

Proliferation of astrocytes is a dramatic response of the central nervous system (CNS) to injury and disease. Such proliferation results in the formation of the neural/glial scar and the reconstitution of the glial limitans. However, not all astrocytes enter the proliferative cycle following injury, and for those that do, the period of cell division is limited. Little attention has focused on the events that regulate the duration and extent of astrocyte proliferation following damage, but clearly control mechanisms are in place as CNS injury does not result in the continuous astrocyte proliferation seen in glial tumorigenesis. Protein tyrosine phosphorylation has been implicated in both astrocyte proliferation and differentiation and plays an important role in the regulation of the cell cycle in a number of different systems. We have found a small subset of astrocytes in the chick auditory brainstem that are immunopositive for the protein tyrosine phosphatase SHP-1. SHP-1 appears to negatively regulate cellular division in the hematopoietic system and is involved in the mitogenic response to various growth factors. Following cochlea removal, there is a marked increase within the auditory brainstem nucleus, nucleus magnocellularis (NM), in both in the number of SHP-1-positive astrocytes and the length of their immunopositive fibers. Significantly, those animals showing the greatest increases in SHP-1 immunoreactivity do not exhibit large amounts of astrocyte proliferation. We hypothesize that the expression of SHP-1 plays a role in negatively regulating the mitotic behavior of astrocytes following deafferentation.

Animals↗
PubMed2000

Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression.

The protein tyrosine phosphatase SHP-1 is predominantly expressed in hemopoietic cell lineages, where its function is relatively well defined. However, its expression profile also extends to certain epithelial cell types. Furthermore, the negative regulatory role of this enzyme in hemopoietic cell signaling may not apply to other systems, where positive effects on particular tyrosine kinase signaling pathways have been described. Expression of SHP-1 was therefore investigated in human breast cancer cell lines and primary breast cancers. Differential expression of SHP-1 mRNA was observed among the 19 breast cancer cell lines examined, and in an analysis of 72 primary breast cancers, SHP-1 mRNA expression was increased 2- to 12-fold relative to normal breast epithelial cells in 58% of the samples. Interestingly, a subset of the cancers also over-expressed GRB2 mRNA by 2- to 7-fold, and a significant (p < 0.01) positive correlation was observed between SHP-1 and GRB2 mRNA expression. Since these proteins can bind to each other and regulate MEK/MAP kinase activation, their co-ordinate up-regulation may amplify tyrosine kinase signaling in breast cancer cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Identification of epidermal growth factor receptor- Grb2-associated binder-1-SHP-2 complex formation and its functional loss during neoplastic cell progression.

The adaptor protein Grb2-associated binder-1 (Gab1) is known to bind to the SHP-2 tyrosine phosphatase on epidermal growth factor (EGF) receptor stimulation. To clarify the roles of these two proteins in EGF receptor (EGFR) signaling and determine their possible alteration during neoplastic cell progression, we studied these proteins in a Syrian hamster embryo (SHE) cell line model of neoplastic progression. Specifically, we used asbestos-transformed SHE fibroblasts: the 10W+8 clone, which is immortal but nontumorigenic; and the 10W2T clone, which is tumorigenic. Gab1 was detected, and the EGF-dependent formation of the EGFR-Gab1-SHP-2 complex was observed in 10W+8 cells. After cloning hamster Gab1 cDNA, exogenous expression of Gab1 significantly enhanced EGF-dependent mitogenic activity in 10W+8 cells. On the other hand, Gab1 was not detected in 10W2T cells, and the EGF-dependent association of SHP-2 with EGFR was also absent. Exogenous Gab1 expression in transfected 10W2T cells restored the EGF-dependent association of SHP-2 with EGFR, although it only showed a marginal effect on EGF-dependent mitogenic activity. Thus, Gab1 plays a pivotal role in the EGFR signaling pathway via the formation of the EGFR-Gab1-SHP-2 complex, and alteration in the expression and function of Gab1 is implicated in the neoplastic progression of SHE cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lack of the protein tyrosine phosphatase SHP-1 results in decreased numbers of glia within the motheaten (me/me) mouse brain.

Mice that are homozygous for the autosomal recessive motheaten allele (me/me) lack the protein tyrosine phosphatase SHP-1. Loss of SHP-1 leads to many hematopoietic abnormalities, as well as defects such as infertility and low body weight. However, little is known regarding the role SHP-1 plays in the development of the central nervous system (CNS). To define the role of SHP-1 in CNS development and differentiation, we examined the brains of me/me mice at various times after birth for neuronal and glial abnormalities. Although the brains of me/me mice are slightly smaller than age-matched wild-type littermates, both me/me and wild-type brains are similar in weight, possess an intact blood-brain barrier, and have largely normal neuronal architecture. Significantly, the current study reveals that me/me brain shows decreases in the number of glial fibriallary acidic protein (GFAP)+ astrocytes and F480+ microglia compared with wild-type mice. In addition, decreased immunostaining for the myelin-synthesizing enzyme CNPase was observed in me/me mice, confirming the loss of myelin in these animals, as reported (Massa et al. [2000] Glia 29:376-385). It is particularly significant that there is a decreased number of immunolabeled glia of all subtypes and that this deficit in glial number is not restricted to a particular class of glia. This suggests that SHP-1 is necessary for the normal differentiation and distribution of astrocytes, microglia, and oligendrocytes within the murine CNS.

Animals↗
PubMed2002

SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.

Fcgamma receptor-mediated phagocytosis is a complex process involving the activation of protein tyrosine kinases, events that are potentially down-regulated by protein tyrosine phosphatases. We used the J774A.1 macrophage cell line to examine the roles played by the protein tyrosine phosphatase SHP-1 in the negative regulation of Fcgamma receptor-mediated phagocytosis. Stimulation with sensitized sheep red blood cells (sRBCs) induced tyrosine phosphorylation of CBL and association of CBL with CRKL. These events were completely or partially abrogated by PP1 or the heterologous expression of dominant-negative SYK, respectively. Heterologous expression of wild-type but not catalytically inactive SHP-1 also completely abrogated the phagocytosis of IgG-sensitized sRBCs. Most notably, overexpressed SHP-1 associates with CBL and this association led to CBL dephosphorylation, loss of the CBL-CRKL interaction, and the suppression of Rac activation. These data represent the first direct evidence that SHP-1 is involved in the regulation of Fcgamma receptor-mediated phagocytosis and suggest that activating signals mediated by SRC family kinases SYK, CBL, phosphatidyl inositol-3 (PI-3) kinase, and Rac are directly opposed by inhibitory signals through SHP-1.

Animals↗
PubMed2003

Angiotensin II blocks nicotine-mediated neuroprotection against beta-amyloid (1-42) via activation of the tyrosine phosphatase SHP-1.

We showed recently that nicotine activates the growth-promoting enzyme Janus kinase 2 (JAK2) in PC12 cells and that preincubation of these cells with the JAK2-specific inhibitor AG-490 blocked the nicotine-induced neuroprotection against beta-amyloid (1-42) [Abeta (1-42)]. These results provided direct evidence for linkage between JAK2 and the alpha7 nicotinic acetylcholine receptor-induced neuroprotection in PC12 cells. We also showed that preincubation with angiotensin II (Ang II), functioning via the angiotensin II type 2 (AT2) receptor, blocked both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42). Recently growth-inhibitory effects of the AT2 receptor have been reported to be mediated by the activation of protein tyrosine phosphatases (PTPases) and that AT2 receptor stimulation is associated with a rapid activation of the PTPase SHP-1 (the cytoplasmic tyrosine phosphatase that contains Src homology 2 domains), a negative regulator of JAK2 signaling. Therefore, the potential biological significance of AT2 receptor-induced effects on both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42) led us to investigate whether SHP-1 activation could be involved in this process. We found that Ang II induced the activation of SHP-1 and that an antisense against SHP-1 not only augmented the nicotine-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of the nicotine-induced neuroprotection. These results demonstrate that nicotine-induced tyrosine phosphorylation of JAK2 and neuroprotection against Abeta (1-42) in PC12 cells are blocked by Ang II via AT2 receptor-induced activation of SHP-1.

Amyloid beta-Peptides↗
PubMed1998

Involvement of SHP-2 in multiple aspects of IL-2 signaling: evidence for a positive regulatory role.

Binding of IL-2 to its receptor activates several biochemical pathways, but precisely how these pathways are linked is incompletely understood. Here, we report that SHP-2, an SH2-domain containing tyrosine phosphatase, associates with different molecules of the IL-2 signaling cascade. Upon IL-2 stimulation, SHP-2 was coimmunoprecipitated with Grb2 and the p85 subunit of phosphatidylinositol 3-kinase. In contrast, SHP-2 was constitutively associated with JAK1 and JAK3. Finally, SHP-2 expression amplified STAT-dependent transcriptional activation whereas a dominant negative allele inhibited transactivation and the IL-2-induced activation of MAPK (mitogen-activated protein kinase). These results demonstrate the involvement of SHP-2 in multiple pathways of the IL-2 signaling cascade and provide evidence for its positive regulatory role.

Adaptor Proteins, Signal Transducing↗
PubMed1998

SHP-1 deficiency in B-lineage cells is associated with heightened lyn protein expression and increased lyn kinase activity.

SHP-1 protein tyrosine phosphatase is a critical regulator of signal transduction in hematopoietic cells. In the present study, we derived two pre-B cell lines, PBCL-1 and PBCL-2, from normal and SHP-1-deficient motheaten mice, respectively, and characterized hyperphosphorylated proteins in PBCL-2 cells to identify SHP-1-regulated molecules. Two proteins of 56 and 53 kDa (p56/p53) in PBCL-2 cells showed heightened phosphorylation (3- to 6-fold) in comparison with those in PBCL-1. p56/p53 were identified as the two forms of the lyn protein tyrosine kinase (p56/p53lyn), which showed increased kinase activity in PBCL-2 cells. Interestingly, the protein levels of p56/53lyn were found to be 3- to 6-fold higher in PBCL-2 cells than those in PBCL-1, whereas the transcript levels of lyn in the two cell lines were comparable. A modest increase in p56/53lyn protein expression was also detected in primary spleen B cells of motheaten mice. Thus SHP-1 deficiency in B-lineage cells, especially pre-B cells, is associated with increased lyn protein expression and kinase activity. These data indicate a role for SHP-1 in regulating lyn through a post-transcriptional mechanism.

Animals↗
PubMed1999

Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling.

SHP-2 is a widely distributed Src homology 2 (SH2) domain-containing tyrosine phosphatase that is recruited to growth factor receptors on stimulation. We have transiently co-expressed several catalytically active and inactive forms of the enzyme with the platelet-derived growth factor (PDGF) receptor in human embryonic kidney 293 cells. The catalytically active forms of SHP-2 decreased the tyrosine phosphorylation of the receptor, whereas the catalytically inactive forms increased the phosphorylation. However, PDGF-induced activation of the mitogen-activated protein (MAP) kinase pathway was enhanced by the active forms of SHP-2 but decreased by the inactive forms. The results suggest that the PDGF receptor is a physiological substrate of SHP-2 and that SHP-2 has a positive role in the PDGF-stimulated activation of MAP kinase. The dissociation of the receptor phosphorylation from the activation of MAP kinase suggests that signalling through growth factor receptors does not depend merely on their tyrosine phosphorylation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2005

SLP-76 is recruited to CD22 and dephosphorylated by SHP-1, thereby regulating B cell receptor-induced c-Jun N-terminal kinase activation.

Despite the important role in the development and activation of T cells, NK cells, mast cells, and macrophages, the expression and function of SLP-76 in B cells have been largely unknown. Here we demonstrate that SLP-76 is expressed in all mouse B cell lines tested and in normal splenic B cells, and serves as an SHP-1 substrate. Dephosphorylation of SLP-76 by SHP-1 inhibits its association with Nck, down-regulating c-Jun N-terminal kinase (JNK) activation and exerting a positive effect on apoptosis. Knockdown of SLP-76 in WEHI-231 cells by small interfering RNA attenuated JNK activation, but showed little effects on extracellular signal-regulated kinase (ERK) or p38 activation. Although WEHI-231 does not express linker for activation of T cells (LAT), SLP-76 localizes in membrane fraction, which increases following B cell receptor (BCR) cross-linking. Further analyses revealed that SLP-76 complexed with Gads is associated with tyrosine-phosphorylated CD22 through the SH2 domains of SLP-76 and Gads. Given that SHP-1 binds to CD22 upon BCR ligation, our findings suggest that dephosphorylation of SLP-76 recruited to CD22 by SHP-1 inhibits BCR-induced JNK activation, dictating apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Tyrosine 1213 of Flt-1 is a major binding site of Nck and SHP-2.

Vascular endothelial growth factor (VEGF) binds to its receptor tyrosine kinase Flt-1 and KDR/Flk-1 and stimulates their autophosphorylation. However, little is known about their downstream signal transduction properties. We examined the interactions of certain proteins with a SH2-domain with Flt-1 and KDR using the yeast two-hybrid system and found that Nck, SHP-2, PLC gamma, and PI3K p85 bind to Flt-1. Extensive site-directed mutagenesis of Flt-1 revealed their major binding sites. Nck, SHP-2, and PI3K bind to Y1213 of Flt-1. Nck also binds to Y1333 of Flt-1. These results suggest that Nck, SHP-2, PLC gamma, and PI3K play important roles in Flt-1 signal transduction and that Y1213 of Flt-1 is a major binding site of PI3K, Nck, and SHP-2.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Epitope mapping of SHP-1 monoclonal antibodies using peptide phage display.

We have characterized the binding epitopes of four monoclonal antibodies for SHP-1, an SH2 domain containing protein tyrosine phosphatase, using two phage displayed random peptide libraries. Three of the antibodies are directed against the phosphatase domain of the molecule and the fourth is toward the NH2-terminal part of the second SH2 domain. The first two antibodies recognize the sequence NANY, amino acid 305 to amino acid 308, numbered in the non haematopoietic form of human SHP-1 sequence. The third antibody binds the sequence P Y W P (amino acids 365 to 368) located toward the middle of the phosphatase domain of the enzyme. The fourth antibody is directed against the first two amino acids, W Y (amino acids 112 and 113), of the second SH2 domain. The specificities of these antibodies are demonstrated by ELISA and western blot using different protein constructs expressed in bacteria. All the antibodies can detect wild type SHP-1, expressed in 293 cells, by western blot analysis, both under denaturing conditions as well as following renaturation. The data presented here show that the antibodies characterized in this study are raised against linear epitopes and suggest that these epitopes are accessible from the outside in the native SHP-1 molecule.

Amino Acid Sequence↗
PubMed2002

Nuclear translocation of SHP and visualization of interaction with HNF-4alpha in living cells.

Mutations in small heterodimer partner (SHP) and hepatocyte nuclear factor 4alpha (HNF4alpha) are associated with mild obesity and diabetes mellitus, respectively. Both receptors work together to determine the normal pancreatic beta-cell function. We examined their subcellular localization and interaction in living cells by tagging them with yellow and cyan variants of green fluorescent protein (GFP) variants. Expressed SHP resided only in the cytoplasm in COS-7 cells which lacks HNF4alpha, but predominantly in the nucleus in insulinoma cells (MIN6). HNF4alpha was localized exclusively in the nuclei of both cells, coexpressed with HNF4alpha in COS-7 cells, redistributed in the nucleus, depending on the amount of HNF4alpha. We found fluorescence resonance energy transfer between GFP-tagged SHP and HNF4alpha, indicating a specific close association between them in the nucleus. The results strongly suggest that SHP exists primarily in the cytoplasm and is translocated into the nucleus on interacting with its nuclear receptor partner HNF4alpha.

Active Transport, Cell Nucleus↗
PubMed2005

SHP-1 promoter 2 methylation in normal epithelial tissues and demethylation in psoriasis.

SHP-1 promoter hypermethylation has been studied in hematopoietic cells and observed only in various types of lymphoma and leukemia. This study reports a contrasting situation in normal epithelial tissues and an association with skin pathogenesis, particularly in psoriasis. We investigated several cell lines, five of them were epithelial and six were hematopoietic, white blood cells from normal, healthy donors, and normal microdissected epithelium of kidney, liver, breast, cervix, lung, prostate, bladder, and skin. Interestingly, promoter 2 hypermethylation was apparent in all epithelial cell lines and tissues. However, distinctive degrees of demethylation were noted in some skin samples. The methylation patterns of each cell line corresponded to their mRNA isoforms, in that isoforms I and II could not be detected with either promoter 1 or 2 hypermethylation, respectively. We further explored whether an enhanced degree of demethylation could be observed in various dermatopathology lesions. While the promoter 2 methylation levels of squamous cell cancers, eczemas, and normal skins were not different, a significant degree of demethylation can be observed in psoriasis (p<0.005). In addition, psoriasis displays a higher level of SHP-1 isoform II than normal skin (p<0.05). In conclusion, this study discovered an unprecedented role of SHP-1 methylation in tissue-specific expression and its alteration in a nonmalignant human disease besides the transcription inhibition in leukemia and lymphoma. Furthermore, the promoter demethylation may play an important role in skin pathogenesis by enhancing SHP-1 isoform II transcription in psoriatic skin lesions.

Cell Line↗