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

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 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.

EphA2 overexpression promotes ovarian cancer growth

“…34 Alternatively, the phosphotyrosine content of EphA2 may also be negatively regulated by associated phosphatases such as LMW-PTP. 35, 36 The effect of EphA2 overexpression was examined in breast cancer by Zelinski and colleagues 9 who demonstrated that EphA2 overexpression was sufficient to confer malignant transformation and tumorigenic potential on non-transformed (MCF-10A) mammary epithelial cells. Nasreen and colleagues reported that EphA2 overexpression significantly enhanced the proliferation and haptotaxis of malignant mesothelioma cells.…”

Loss of Zap-70 and low molecular weight phosphotyrosine phosphatase occurs after therapy in a patient with B-chronic lymphocytic leukemia

“…1 These cells provide growth factors, cell-to-cell interaction, and matrix proteins that play an important role in the regulation of haematopoiesis, and many of these cells may be derived from a common precursorthe mesenchymal stem cell (MSC). 2,3 It is therefore that the MSC population may serve as a facilitator of haematopoietic engraftment in clinical haematopoietic stem cell transplantation 4 as well as a good springboard for further studies of how stroma influences haematopoiesis. 5 It is currently recognized that the microenvironment in which a cancer cell grows comprises a critical component of the malignant disease process.…”

“…Although not well characterized in chronic lymphocytic leukemia, overexpression of LMWPTP is generally associated with a proliferative phenotype. 4 LMWPTP has been shown to interact with several tyrosine kinases including the platelet-derived growth factor receptor, the macrophage colony-stimulating factor receptor, the insulin receptor, the Eph receptor, and the epidermal growth factor receptor. 5 Since LMWPTP also interacts with Zap-70, 3 we followed the expression of activated Zap-70 and LMWPTP in a patient with chronic lymphocytic leukemia.…”

Low Molecular Weight Protein Tyrosine Phosphatases Control Antibiotic Production in Streptomyces coelicolor A3(2)

“…Eukaryotic LMW PTPs play an important role in signal transduction mainly by specifically dephosphorylating and downregulating tyrosine kinase receptors such as the PDGF receptor or insulin receptor [37]. In S. cerevisiae heterologous overexpression of a LMW-PTP, Stp1, (from Schizosaccharomyces pombe) resulted in a large number of phenotypes that indicated down-regulation of the Ras pathway [38].…”

“…Comparison of physiological behavior of the ptpA and sco3700 over expression strains and possible regulatory effects Dephosphorylation of proteins can mediate both activation and inactivation of target proteins, and by consequence physiological functions [37]. Overexpression of ptpA and sco3700 affected antibiotic production in S. coelicolor differently.…”