Synergy in tumor suppression by direct interaction of Neutral Endopeptidase with PTEN

Sumitomo, Makoto; Iwase, Akira; Zheng, Rong; Navarro, Daniel; Kaminetzsky, David; Shen, Ruoqian; Georgescu, Maria Magdalena; Nanus, David M.

doi:10.1016/s1535-6108(03)00331-3

Cited by 99 publications

(98 citation statements)

References 34 publications

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“…Loss of expression of other membrane associated peptidases such as CD10/NEP, CD13/APN, and BP-1/6C3/APA has been reported in several types of human cancers (43)(44)(45). Recently, neutral endopeptidase has been shown to interact directly with the tumor suppressor gene, pTEN and block FAK signaling pathway thereby functioning as a tumor suppressor gene for prostate cancer cells (45).…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

2005

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Dipeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogenactivated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinasetype plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway. (Cancer Res 2005; 65(4): 1325-34)

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Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

2005

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“…In fact, PTEN has also been found to directly translocate to the plasma membrane in certain cell lines and under specifi c conditions 3,20,31 . Our fi nding that SUMO1 modifi cation of PTEN increases PTEN binding to the plasma membrane ( Figs 4, 5 and 7 ) may explain why a small fraction of PTEN acts through the dynamic interaction with the inner face of plasma membrane 2 .…”

Section: E N T I -V E C T O R L E N T I -V E C T O R Kdamentioning

confidence: 99%

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

et al. 2012

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The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase / AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modifi ed by SUMO1 at both K 266 and K 254 sites in the C2 domain of PTEN. SUMO1 modifi cation at K 266 located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase / AKT pathway and consequently, suppression of anchorageindependent cell proliferation and tumour growth in vivo . Our data demonstrate a molecular mechanism whereby SUMO1 modifi cation is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase / AKT pathway.

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“…PI3K generates phosphatidylinositol-3,4,5-triphosphate (PIP3), which activates multiple downstream effectors including Akt, by phosphorylating phosphatidylinositol-4,5-biphosphate (PIP2) [8]. Such activation is correlated with cell survival in a wide variety of cells, including those of epithelial, mesenchymal and neuronal origin [9,10], as well as cancer cells [11]. In bovine granulosa cells, Akt, a downstream substrate of PI3K, was necessary for the protective effect of IGF-1 against FasL-induced apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

PTEN and Akt expression during growth of human ovarian follicles

Goto

Iwase

Ando

et al. 2007

J Assist Reprod Genet

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Purpose To assess the expression of PTEN and total and phosphorylated Akt in human ovarian follicles during follicular growth. Methods Immunohistochemistry of ovarian tissues and Western blotting and immunofluorescence of primary cultured luteinized granulosa cells for PTEN and Akt. Results Immunoreactivity of Akt was found in the oocytes, granulosa cells and theca cells in primordial follicles, follicles at each growing stage and luteal cells. As the follicles grew, staining for PTEN became intense in the granulosa cells, whereas the intensity of phospho-Akt became weak. Western blotting and immunofluorescence analysis using primary cultured granulosa-lutein cells showed Akt and PTEN expression, and phosphorylation of Akt in vitro. Conclusions PTEN and Akt are present in the granulosa cells during folliculogenesis. An increase in PTEN may lead to changes in proliferation and/or differentiation of granulosa cells during follicular growth via regulation of Akt phosphorylation.

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Synergy in tumor suppression by direct interaction of Neutral Endopeptidase with PTEN

Cited by 99 publications

References 34 publications

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane

PTEN and Akt expression during growth of human ovarian follicles

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