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

Oncogene volume 23, pages 3905–3914 (2004)Cite this article

Abstract

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 β-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 β-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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Acknowledgements

This work was supported by the Italian Association for Cancer Research (AIRC), by the Ministero Italiano della Università e Ricerca (MIUR-PRIN 2001 to SC and 2002 to GR), by Ministero della Salute (to SC), in part by Consorzio Interuniversitario Biotecnologie (to GR), in part by Cassa di Risparmio di Firenze (to PC and SC), and in part by Consiglio Nazionale delle Ricerche (Progetto Finalizzato Oncologia to SC). The authors are very grateful to Professor Mary Forrest for accurate revision of the paper.

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  1. Paola Chiarugi, Giovanni Raugei and Giampietro Ramponi: Center for Research, Transfer and High Education ‘Study at Molecular and Clinical Level of Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development on Novel Therapies’

Authors and Affiliations

  1. Department of Biochemical Sciences of the University of Florence, viale Morgagni 50, Firenze, 50134, Italy

    Paola Chiarugi, Maria Letizia Taddei, Elisa Giannoni, Tania Fiaschi, Giovanni Raugei & Giampietro Ramponi

  2. Department of Experimental Pathology and Oncology, University of Florence, Italy

    Nicola Schiavone, Laura Papucci & Sergio Capaccioli

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  1. Paola Chiarugi
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  2. Maria Letizia Taddei
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Correspondence to Giovanni Raugei.

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Chiarugi, P., Taddei, M., Schiavone, N. et al. LMW-PTP is a positive regulator of tumor onset and growth. Oncogene 23, 3905–3914 (2004). https://doi.org/10.1038/sj.onc.1207508

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