LMW-PTP Is a Negative Regulator of Insulin-Mediated Mitotic and Metabolic Signalling

Chiarugi, Paola; Cirri, Paolo; Marra, Fabio; Raugei, Giovanni; Camici, Giovanni G.; Manao, Giampaolo; Ramponi, Giampietro

doi:10.1006/bbrc.1997.7355

Cited by 104 publications

(96 citation statements)

References 31 publications

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“…We previously reported that in in vitro NIH3T3 cells PDGF-R and b-catenin are efficiently dephosphorylated by the phosphatase, thus correlating with decreased PDGF-mediated proliferation rate and increased cadherin/b-catenin cell adhesion, respectively (Chiarugi et al, 1997;Taddei et al, 2002). On the other hand, in fibrosarcomas neither PDGF-R nor b-catenin are dephosphorylated by LMW-PTP which is conversely active on EphA2 receptor.…”

Section: Discussionmentioning

confidence: 97%

“…By means of wt and dnLMW-PTP overexpression, we and others suggest both negative and positive roles for LMW-PTP. In particular, in in vitro cell cultures LMW-PTP negatively influences PDGF-R (Chiarugi et al, 1995), fibroblast growth factor receptor (Rigacci et al, 1999), epidermal growth factor receptor (Ramponi et al, 1989) and insulin receptor signaling (Chiarugi et al, 1997), and positively affects EphA2 (Kikawa et al, 2002) and EphB1 signaling (Stein et al, 1998). Similar to LMW-PTP, SHP-2 has been proposed for both a positive and negative role in signal transduction (Ronnstrand and Heldin, 2001).…”

Section: Discussionmentioning

confidence: 99%

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LMW-PTP is a positive regulator of tumor onset and growth

et al. 2004

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Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are an enzyme family that plays a key role in cell proliferation control by dephosphorylating/ inactivating both tyrosine kinase receptors (such as PDGF, insulin, and ephrin receptors) and docking proteins (such, as b-catenin) endowed with both adhesion and transcriptional activity. Besides being a frequent event in human tumors, overexpression of LMW-PTP has been recently demonstrated to be sufficient to induce neoplastic transformation. We recently demonstrated that overexpression of LMW-PTP strongly potentiates the stability of cell-cell contacts at the adherens junction level, which powerfully suggests that LMW-PTP may also contribute to cancer invasivity. Focusing on mechanisms by which LMW-PTP is involved in cancer onset and progression, the emerging picture is that LMW-PTP strongly increases fibronectin-mediated cell adhesion and mobility but, paradoxically, decreases cell proliferation. Nevertheless, LMW-PTP-transfected NIH3T3 fibroblasts engrafted in nude mice induce the onset of larger fibrosarcomas, which are endowed with higher proliferation activity as compared to mock-transfected controls. Quite opposite effects have been obtained with engrafted fibroblasts transfected with a dominant-negative form of LMW-PTP. Notably, in sarcoma extracts, LMW-PTP overexpression greatly influences the ephrin A2 (EphA2) but not PDGF receptor or b-catenin tyrosine phosphorylation. The high association of dephosphorylated EphA2 overexpression with most human cancers and our observation that cell growth stimulation by LMW-PTP overexpression is restricted to the in vivo model, strongly suggest that LMW-PTP oncogenic potential is mediated by its EphA2 tyrosine dephosphorylating activity.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

LMW-PTP is a positive regulator of tumor onset and growth

et al. 2004

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“…Phosphorylated tyrosine residues on the EphA2 receptor were thought to play a critical role in the recruitment of SH2 or PTB domain-containing signaling molecules, such as the p85 subunit of PI 3-kinase (24), adaptor proteins SLAP (34) and Shc (35), tyrosine phosphatase SHP-2 (36) and low molecular weight protein-tyrosine phosphatase (37,38), ubiquitin ligase c-Cbl (39,40), and guanine nucleotide exchange factors Vav2 and Vav3 (23). In the endothelial cells, we have previously shown that either PI 3-kinase inhibitors or a dominant negative p85 mutant significantly inhibited ephrin-A1 ligand-induced endothelial cell migration (17).…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase

Fang

Brantley-Sieders

Hwang

et al. 2008

Journal of Biological Chemistry

105

113

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EphA2 is a member of the Eph family of receptor tyrosine kinases. EphA2 mediates cell-cell communication and plays critical roles in a number of physiological and pathologic responses. We have previously shown that EphA2 is a key regulator of tumor angiogenesis and that tyrosine phosphorylation regulates EphA2 signaling. To understand the role of EphA2 phosphorylation, we have mapped phosphorylated tyrosines within the intracellular region of EphA2 by a combination of mass spectrometry analysis and phosphopeptide mapping using two-dimensional chromatography in conjunction with site-directed mutagenesis. The function of these phosphorylated tyrosine residues was assessed by mutational analysis using EphA2-null endothelial cells reconstituted with

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“…Acid phosphatase locus 1 (ACP1) is an enzyme involved in the signal transduction of insulin and other growth factors (Dissing 1993, Bottini et al 1995, Chiarugi et al 1997, Ramponi & Stefani 1997. ACP1 is encoded at a locus on chromosome 2 showing three common alleles *A, *B and *C (Dissing 1993, Bottini et al 1995.…”

Section: Introductionmentioning

confidence: 99%

“…There are quantitative differences in total enzymatic activity and F/S ratio among ACP1 genotypes (see Bottini et al 1995 for a review). In vitro experiments have shown that ACP1 down-regulates insulin receptor signal transduction (Chiarugi et al 1997), and the ACP1 polymorphism has been found to be associated with glycemic levels in all forms of diabetes (Gloria-Bottini et al 1996, Lucarini et al 1998. These observations prompted us to examine the possible effect of ACP1 enzymatic variability on the results of GH stimulation by insulin in growthretarded children.…”

Section: Introductionmentioning

confidence: 99%

The genetics of signal transduction and the outcome of diagnostic tests in growth retardation

Bottini

Lucarini²,

Amante³

et al. 2001

Journal of Endocrinology

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The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0·02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0·005) and to react more promptly than the genotypes with high S isoform concentrations (P<0·05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.

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LMW-PTP Is a Negative Regulator of Insulin-Mediated Mitotic and Metabolic Signalling

Cited by 104 publications

References 31 publications

LMW-PTP is a positive regulator of tumor onset and growth

LMW-PTP is a positive regulator of tumor onset and growth

Identification and Functional Analysis of Phosphorylated Tyrosine Residues within EphA2 Receptor Tyrosine Kinase

The genetics of signal transduction and the outcome of diagnostic tests in growth retardation

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