A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

Ramesh, Mathangi; Krishnan, Navasona; Muthuswamy, Senthil K.; Tonks, Nicholas K.

doi:10.1074/jbc.m114.627968

Cited by 11 publications

(11 citation statements)

References 55 publications

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“…Our laboratory performed RNAi-mediated loss-of-function screens to test the effects of suppressing systematically the expression of PTP family members in threedimensional cell culture models. We identified several PTPs as novel negative and positive regulators of HER2 signaling in the control of cell polarity, migration, and invasion (Lin et al 2011;Ramesh et al 2015). Interestingly, only PTPN23 was shown to inhibit mammary epithelial cell motility and invasion in a HER2-independent manner by impairing the integrity of adheren junctions through regulating the phosphorylation status of E-cadherin and β-catenin (Lin et al 2011).…”

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confidence: 99%

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

et al. 2017

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Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. () resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. In a loss-of-function PTPome screen, our laboratory identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. Now, our TCGA (The Cancer Genome Atlas) database analyses illustrate a correlation between low PTPN23 expression and poor survival in breast cancers of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1Dβ cells induced breast tumors within 56 wk. In PTPN23-depleted tumors, we detected hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN as well as Tyr142 in β-catenin. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis as that of a key phosphatase that normally suppresses the activity of FYN in two different models. We demonstrated that tumor outgrowth from PTPN23-deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, double knockout of and via CRISPR/CAS9 also attenuated tumor outgrowth from knockout Cal51 cells. Overall, this mechanistic analysis of the tumor-suppressive function of PTPN23 in breast cancer supports the identification of FYN as a therapeutic target for breast tumors with heterozygous or homozygous loss of.

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Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

et al. 2017

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“…In absence of Tie-2, VE-PTP inhibition destabilized endothelial junctions suggesting a functional role for Tie-2 in barrier regulation in the absence of VEcadherin [71]. In this study, we identified a novel role for PTPN14, a PLD2 dependent non-receptor PTP [24], in regulating thrombin-induced VEcadherin stabilization in AJs in human lung ECs. Our study clearly demonstrates that the activity of PTPN14 is essential for stabilization of VE-cadherin at AJs through dephosphorylation of VE-cadherin during thrombin-induced endothelial barrier recovery of lung ECs.…”

Section: Discussionmentioning

confidence: 72%

“…PTPN14 was identified as a major phosphatase of epithelial and endothelial cell AJs and dominant negative PTPN14 (Pez) mutant enhanced cell motility suggesting potential regulation by PTPN14 through its action on cell-cell adhesion (73). Interestingly, PTPN14 is a positive regulator of ERBB2 signaling in mammary epithelial cells, which is dependent on PLD2 dependent (24) and in cancer cells PTPN14 promoted proliferation and migration through the regulation of Hippo/YAP signaling pathway (74).…”

Section: Discussionmentioning

confidence: 99%

“…Having demonstrated a key role for PLD2-generated PA in VE-cadherin Y658 phosphorylation/dephosphorylation status after thrombin stimulation of HLMVECs or LPS challenge in MLMVECs, next we investigated the role of PTPN14, a PLD2/PA dependent PTP, in VEcadherin dephosphorylation following thrombin stimulation. A recent study identified the regulation of PTPN14 by PLD2-mediated production of PA in the stimulation of ERBB2 signaling in mammary epithelial MCF10A cells (24). To investigate the role of PTPN14 in endothelial barrier function, HLMVECs were transfected with scrambled or PTPN14 siRNA.…”

Section: Depletion Of Ptpn14 a Pa-dependent Ptp Retards Ve-cadherinmentioning

confidence: 99%

“…However, the biological functions of PTPN14 and its target(s) remain poorly characterized. A recent study has demonstrated that the lipid second messenger, phosphatidic acid (PA), binds to PTPN14 in vitro and enhances its catalytic activity, and this interaction was implicated in mammary epithelial cell morphogenesis (24). Very little is known on the role of PTPN14 in endothelial function and barrier regulation.…”

Section: Introductionmentioning

confidence: 99%

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Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

Ramchandran

Shaaya

et al. 2020

Journal of Biological Chemistry

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Increased permeability of vascular lung tissues is a hallmark of acute lung injury and is often caused by edemagenic insults resulting in inflammation. Vascular endothelial (VE)-cadherin undergoes internalization in response to inflammatory stimuli and is recycled at cell adhesion junctions during endothelial barrier re-establishment. Here, we hypothesized that phospholipase D (PLD)-generated phosphatidic acid (PA) signaling regulates VE-cadherin recycling and promotes endothelial barrier recovery by dephosphorylating VE-cadherin. Genetic deletion of PLD2 impaired recovery from protease-activated receptor-1–activating peptide (PAR-1–AP)-induced lung vascular permeability and potentiated inflammation in vivo. In human lung microvascular endothelial cells (HLMVECs), inhibition or deletion of PLD2, but not of PLD1, delayed endothelial barrier recovery after thrombin stimulation. Thrombin stimulation of HLMVECs increased co-localization of PLD2-generated PA and VE-cadherin at cell-cell adhesion junctions. Inhibition of PLD2 activity resulted in prolonged phosphorylation of Tyr-658 in VE-cadherin during the recovery phase 3 h post-thrombin challenge. Immunoprecipitation experiments revealed that after HLMVECs are thrombin stimulated, PLD2, VE-cadherin, and protein-tyrosine phosphatase nonreceptor type 14 (PTPN14), a PLD2-dependent protein-tyrosine phosphatase, strongly associate with each other. PTPN14 depletion delayed VE-cadherin dephosphorylation, reannealing of adherens junctions, and barrier function recovery. PLD2 inhibition attenuated PTPN14 activity and reversed PTPN14-dependent VE-cadherin dephosphorylation after thrombin stimulation. Our findings indicate that PLD2 promotes PTPN14-mediated dephosphorylation of VE-cadherin and that redistribution of VE-cadherin at adherens junctions is essential for recovery of endothelial barrier function after an edemagenic insult.

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Scalable network estimation withL₀penalty

Kim

Zhu

Wang

et al. 2020

Statistical Analysis

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With the advent of high-throughput sequencing, an efficient computing strategy is required to deal with large genomic data sets. The challenge of estimating a large precision matrix has garnered substantial research attention for its direct application to discriminant analyses and graphical models. Most existing methods either use a lasso-type penalty that may lead to biased estimators or are computationally intensive, which prevents their applications to very large graphs. We propose using an L 0 penalty to estimate an ultra-large precision matrix (scalnetL0). We apply scalnetL0 to RNA-seq data from breast cancer patients represented in The Cancer Genome Atlas and find improved accuracy of classifications for survival times. The estimated precision matrix provides information about a large-scale co-expression network in breast cancer. Simulation studies demonstrate that scalnetL0 provides more accurate and efficient estimators, yielding shorter CPU time and less Frobenius loss on sparse learning for large-scale precision matrix estimation. K E Y W O R D S L 0 penalty, genomics, network, scalable 1 INTRODUCTION With the advent of high-throughput sequencing, an efficient computing strategy is required to deal with larger and denser genomic data. The challenge of estimating a Abbreviations: scalnetL0, scalable network estimation with L 0 penalty; TCGA, The Cancer Genome Atlas. large precision matrix has garnered substantial research attention for its direct application to classification and discriminant analyses [12, 5, 10]. For example, we can predict whether individual patients with breast cancer will experience long or short survival times using their gene

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A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

Cited by 11 publications

References 55 publications

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

Scalable network estimation withL₀penalty

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A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

Cited by 11 publications

References 55 publications

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

Scalable network estimation withL0penalty

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Scalable network estimation withL₀penalty