Activation of Src by Protein Tyrosine Phosphatase 1B Is Required for ErbB2 Transformation of Human Breast Epithelial Cells

Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Cancer Research (Impact Factor: 9.33). 06/2009; 69(11):4582-8. DOI: 10.1158/0008-5472.CAN-08-4001
Source: PubMed


Protein tyrosine phosphatase (PTP) 1B plays a major role in inhibiting signaling from the insulin and leptin receptors. Recently, PTP1B was found to have an unexpected positive role in ErbB2 signaling in a mouse model of breast cancer, but the mechanism underlying this effect has been unclear. Using human breast epithelial cells grown in a three-dimensional matrix, we found that PTP1B, but not the closely related enzyme T-cell PTP, is required for ErbB2 transformation in vitro. Activation of ErbB2, but not ErbB1, increases PTP1B expression, and increased expression of PTP1B activates Src and induces a Src-dependent transformed phenotype. These findings identify a molecular mechanism by which PTP1B links an important oncogenic receptor tyrosine kinase to signaling pathways that promote aberrant cell division and survival in human breast epithelial cells.

Download full-text


Available from: Luis E Arias-Romero,
  • Source
    • "With over 100 PTP family members, increasing numbers are known to play direct roles in tumour cell biology [7,9–11]. While historically regarded as tumour suppressors, a third of the tyrosine phosphatome may positively contribute to cancer cell survival and therapeutic resistance as shown in HeLa cells [12], and moreover there are recently-defined examples of specific tumour-supporting PTPs [13] [14] [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Cancer Letters 02/2015; 357(1):316-27. DOI:10.1016/j.canlet.2014.11.039 · 5.62 Impact Factor
  • Source
    • "Vascular remodeling processes are multicellular events with a highly organized time course and numerous signaling pathways involved. Several PTPs like PTP1B and SHP-2 have been implicated in positively regulating PDGF-βR-dependent c-src and VEGFR2 mediated Akt and c-src activation and receptor-independent activation of Ras [26, 42, 43]. Indeed, Oshikawa et al. demonstrated siRNA against DEP-1 resulting in enhanced VEGF-induced VEGFR2 tyrosine phosphorylation [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Collateral growth, arteriogenesis, represents a proliferative mechanism involving endothelial cells, smooth muscle cells, and monocytes/macrophages. Here we investigated the role of Density-Enhanced Phosphatase-1 (DEP-1) in arteriogenesis in vivo, a protein-tyrosine-phosphatase that has controversially been discussed with regard to vascular cell biology. Wild-type C57BL/6 mice subjected to permanent left common carotid artery occlusion (CCAO) developed a significant diameter increase in distinct arteries of the circle of Willis, especially in the anterior cerebral artery. Analyzing the impact of loss of DEP-1 function, induction of collateralization was quantified after CCAO and hindlimb femoral artery ligation comparing wild-type and DEP-1(-/-) mice. Both cerebral collateralization assessed by latex perfusion and peripheral vessel growth in the femoral artery determined by microsphere perfusion and micro-CT analysis were not altered in DEP-1(-/-) compared to wild-type mice. Cerebrovascular reserve capacity, however, was significantly impaired in DEP-1(-/-) mice. Cerebrovascular transcriptional analysis of proarteriogenic growth factors and receptors showed specifically reduced transcripts of PDGF-B. SiRNA knockdown of DEP-1 in endothelial cells in vitro also resulted in significant PDGF-B downregulation, providing further evidence for DEP-1 in PDGF-B gene regulation. In summary, our data support the notion of DEP-1 as positive functional regulator in vascular cerebral arteriogenesis, involving differential PDGF-B gene expression.
    08/2013; 2013(3):802149. DOI:10.1155/2013/802149
  • Source
    • "In contrast, ß-catenin from hippocampi of KO animals showed a significant increase in phosphorylation of Tyr-654 (Figure 5A). In contrast, levels of phospho-Erk decreased in KO animals consistent with previous studies (Figure S2) [47]–[49]. It was previously shown that phosphorylation of ß-catenin by pp60c-src significantly decreased the affinity for E-cadherin, decreasing the association constant by 5-fold [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates ß-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP-PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP-PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ß-catenin-Tyr-654 phosphorylation increased ∼5-fold in the hippocampus of adult PTP1B(-/-) (KO) mice compared to wild type (WT) mice and this was accompanied by a reduction in the amount of ß-catenin associated with N-cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1B(fl/fl)-Emx1-Cre). PTP1B(fl/fl)-Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole), utilized a more efficient strategy (cued), and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of ß-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase.
    PLoS ONE 07/2012; 7(7):e41536. DOI:10.1371/journal.pone.0041536 · 3.23 Impact Factor
Show more