Low molecular weight protein tyrosine phosphatases: Small, but smart

Dipartimento di Scienze Biochimiche, Firenze, Italy.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 07/2002; 59(6):941-9. DOI: 10.1007/s00018-002-8481-z
Source: PubMed


Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are a family of 18-kDa enzymes involved in cell growth regulation. Despite very limited sequence similarity to the PTP superfamily, they display a conserved signature motif in the catalytic site. LMW-PTP associates and dephosphorylate many growth factor receptors, such as platelet-derived growth factor receptor (PDGF-r), insulin receptor and ephrin receptor, thus downregulating many of the tyrosine kinase receptor functions that lead to cell division. In particular, LMW-PTP acts on both growth-factor-induced mitosis, through dephosphorylation of activated PDGF-r, and on cytoskeleton rearrangement, through dephosphorylation of p190RhoGAP and the consequent regulation of the small GTPase Rho. LMW-PTP activity is modulated by tyrosine phosphorylation on two specific residues, each of them with specific characteristics. LMW-PTP activity on specific substrates depends also on its localization. Moreover, LMW-PTP is reversibly oxidized during growth factor signaling, leading to inhibition of its enzymatic activity. Recovery of phosphatase activity depends on the availability of reduced glutathione and involves the formation of an S-S bridge between the two catalytic site cysteines. Furthermore, studies on the redox state of LMW-PTP in contact-inhibited cells and in mature myoblasts suggest that LMW-PTP is a general and versatile modulator of growth inhibition.

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    • "PHACTR1 has been demonstrated to be an important modulator in the pathophysiology of cardiovascular disease [9], and it may be involved in the formation of stenosis in cardiac vessels of CAD [10]. Acid phosphatase locus 1 (ACP1) is a member of the phosphotyrosine protein phosphatase family of proteins and is involved in metabolic signaling [11], growth signaling [12], immunological diseases [13] and cancer development [14]. ACP1 controls the synthesis of an enzyme involved in important metabolic functions [15]. "
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    ABSTRACT: Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.
    International Journal of Molecular Sciences 08/2014; 15(8):14058-76. DOI:10.3390/ijms150814058 · 2.86 Impact Factor
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    • "The active site, or P-loop, of LMW-PTPs has the conserved sequence CLGNICR, conforming to the general PTP sequence CX 5 R [5] [11]. The cysteine residue performs the nucleophilic attack on the phosphorus atom of the substrate phosphate group, producing a covalent phosphoenzyme intermediate [12] [13]. "
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    ABSTRACT: Entamoeba histolytica is a eukaryotic intestinal parasite of humans, and is endemic in developing countries. We have characterized the E. histolytica putative low molecular weight protein tyrosine phosphatase (LMW-PTP). The structure for this amebic tyrosine phosphatase was solved, showing the ligand-induced conformational changes necessary for binding of substrate. In amebae, it was expressed at low but detectable levels as detected by immunoprecipitation followed by immunoblotting. A mutant LMW-PTP protein in which the catalytic cysteine in the active site was replaced with a serine lacked phosphatase activity, and was used to identify a number of trapped putative substrate proteins via mass spectrometry analysis. Seven of these putative substrate protein genes were cloned with an epitope tag and overexpressed in amebae. Five of these seven putative substrate proteins were demonstrated to interact specifically with the mutant LMW-PTP. This is the first biochemical study of a small tyrosine phosphatase in Entamoeba, and sets the stage for understanding its role in amebic biology and pathogenesis.
    Molecular and Biochemical Parasitology 02/2014; 193(1):33-44. DOI:10.1016/j.molbiopara.2014.01.003 · 1.79 Impact Factor
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    • "The 2 isoforms may have different roles in the progression of oncologic pathology [2,3]: the fast isoform is involved on migration, invasion and cell adhesion, catalysing the transformation of different substrates after platelet derived growth factor receptor (PDGF-R) stimulation, whilst the slow isoform, acting directly on PDGF-R, has growth factor receptors as substrates, eg platelet derived growth factor receptor (PDGF), leading to a decrease of cellular growth via its dephosphorylation [3]. LMW-PTP has been largely considered a negative regulator of growth factor-induced cell proliferation, although in some instances it acts as a positive regulator. "
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    ABSTRACT: Low molecular weight protein tyrosine phosphatase (LMW-PTP) has been associated with cell proliferation control through dephosphorylation and inactivation of growth factor receptors such as PDGF-R and EphA2, and with cellular adhesion and migration through p190RhoGap and RhoA. We aim to clarify the role of two main LMW-PTP isoforms in breast cancer tumorigenesis. We used a siRNA-mediated loss-of-function in MDA-MB-435 breast cancer cell line to study the role of the two main LMW-PTP isoforms, fast and slow, in breast cancer tumorigenesis and migration. Our results show that the siRNAs directed against total LMW-PTP and LMW-PTP slow isoform enhanced cell motility in an invasive breast cancer cell line, MDA-MB-435, with no changes in the proliferation and invasive potential of cells. The total LMW-PTP knockdown caused a more pronounced increase of cell migration. Suppression of total LMW-PTP decreased RhoA activation and suppression of the LMW-PTP slow isoform caused a small but significant increase in RhoA activation. We propose that the increase or decrease in RhoA activation induces changes in stress fibers formation and consequently alter the adhesive and migratory potential of cells. These findings suggest that the two main isoforms of LMW-PTP may act differentially, with the fast isoform having a more prominent role in tumor cell migration. In addition, our results highlight functional specificity among LMW-PTP isoforms, suggesting hitherto unknown roles for these proteins in breast cancer biology. Novel therapeutic approaches targeting LMW-PTP, considering the expression of these two isoforms and not LMW-PTP as a whole, should be investigated.
    PLoS ONE 09/2013; 8(9):e76307. DOI:10.1371/journal.pone.0076307 · 3.23 Impact Factor
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