Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis

We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.

Download Full-text

The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance

Cells ◽

10.3390/cells8030265 ◽

2019 ◽

Vol 8 (3) ◽

pp. 265 ◽

Cited By ~ 4

Author(s):

Sathish Murali ◽

Takwa Aroankins ◽

Hanne Moeller ◽

Robert Fenton

Keyword(s):

Collecting Duct ◽

Water Channel ◽

Mouse Kidney ◽

Body Water ◽

Mrna Levels ◽

E3 Ligases ◽

Water Homeostasis ◽

And Function

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function. Although several protein kinases, phosphatases, and ubiquitin E3 ligases have been implicated in AQP2 PTM, how AQP2 is deubiquitylated or the role of deubiquitylases (DUBS) in AQP2 function is unknown. Here, we report a novel role of the ubiquitin-specific protease USP4 in modulating AQP2 function. USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP. AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2. In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP-induced cAMP production were detected. VP-induced AQP2 membrane accumulation in knockdown cells was significantly reduced, which was associated with higher levels of ubiquitylated AQP2. AQP2 protein half-life was also significantly reduced in USP4 knockdown cells. Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment. These studies have implications for understanding body water homeostasis.

Download Full-text

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m114.617092 ◽

2015 ◽

Vol 290 (19) ◽

pp. 12048-12057 ◽

Cited By ~ 15

Author(s):

Chao Liu ◽

Francis Chee Kuan Tan ◽

Zhi-Cheng Xiao ◽

Gavin S. Dawe

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Sodium Channel ◽

Surface Expression ◽

Precursor Protein ◽

Cell Surface Expression

Download Full-text

Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells

Thrombosis and Haemostasis ◽

10.1160/th06-07-0393 ◽

2006 ◽

Vol 96 (12) ◽

pp. 789-793 ◽

Cited By ~ 17

Author(s):

Kamran Bakhtiari ◽

Mark Dessing ◽

Cornelis van ’t Veer ◽

C. Spek ◽

Michael Tanck ◽

...

Keyword(s):

Ethyl Pyruvate ◽

Activated Protein C ◽

Severe Infection ◽

Surface Expression ◽

Mrna Levels ◽

Monocytic Cells ◽

Inflammatory Protein ◽

Anti Inflammatory ◽

And Function

SummarySepsis is characterized by a concurrent activation of inflammation and coagulation. Recently, recombinant human activated protein C was shown to decrease mortality in patients with severe sepsis presumably due to a combined anti-inflammatory and anticoagulant effect.These promising findings led to a search for other products that influence both the inflammatory and the procoagulant response to severe infection. Ethyl pyruvate (EP) was recently identified as an experimental anti-inflammatory agent during endotoxemia and sepsis. The aim of the present study was to investigate whether EP influences coagulation besides its anti-inflammatory effects. For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures. EP dose-dependently inhibited the production of tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1α and MIP-1β by lipopolysaccharide (LPS)-stimulated THP-1 cells at mRNA and protein level, thereby confirming its anti-inflammatory properties in this in-vitro system.In addition, EP dose-dependently attenuated the increases in TF mRNA levels,TF-protein-surface expression and cell-surface-associated TF activity in LPS-stimulated THP-1 cells. These results demonstrate for the first time that EP is a compound with combined anti-inflammatory and anticoagulant effects.

Download Full-text

Transformation by the v-fms oncogene product: role of glycosylational processing and cell surface expression

Molecular and Cellular Biology ◽

10.1128/mcb.5.12.3467-3475.1985 ◽

1985 ◽

Vol 5 (12) ◽

pp. 3467-3475

Author(s):

E J Nichols ◽

R Manger ◽

S Hakomori ◽

A Herscovics ◽

L R Rohrschneider

Keyword(s):

Cell Surface ◽

Gene Product ◽

Early Stage ◽

Surface Expression ◽

Cell Surface Expression ◽

Sarcoma Virus ◽

Complete Processing ◽

Oncogene Protein

The effect of glycosylational-processing inhibitors on the synthesis, cell surface expression, endocytosis, and transforming function of the v-fms oncogene protein (gp140fms) was examined in McDonough feline sarcoma virus-transformed Fischer rat embryo (SM-FRE) cells. Swainsonine (SW), a mannosidase II inhibitor, blocked complete processing, but an abnormal v-fms protein containing hybrid carbohydrate structures was expressed on the cell surface. SW-treated SM-FRE cells retained the transformed phenotype. In contrast, two glucosidase I inhibitors (castanospermine [CA] and N-methyl-1-deoxynojirimycin [MdN]) blocked carbohydrate remodeling at an early stage within the endoplasmic reticulum and prevented cell surface expression of v-fms proteins. CA-treated SM-FRE cells reverted to the normal phenotype. Neither SW, CA, nor MdN affected either endocytosis or the tyrosine kinase activity associated with the v-fms gene product in vitro. These results demonstrate the necessity of carbohydrate processing for cell surface expression of the v-fms gene product and illustrate the unique ability to modulate the transformed state of SM-FRE cells with the glycosylational-processing inhibitors CA and MdN.

Download Full-text

Involvement of LFA-1 in lymphoma invasion and metastasis demonstrated with LFA-1-deficient mutants.

The Journal of Cell Biology ◽

10.1083/jcb.108.5.1979 ◽

1989 ◽

Vol 108 (5) ◽

pp. 1979-1985 ◽

Cited By ~ 74

Author(s):

F F Roossien ◽

D de Rijk ◽

A Bikker ◽

E Roos

Keyword(s):

Cell Surface ◽

Surface Protein ◽

Metastatic Potential ◽

Surface Expression ◽

Cell Surface Expression ◽

Lymphocyte Function ◽

Lymphoma Cells ◽

Mutant Cells

Lymphocyte function-associated antigen-1 (LFA-1) is a leukocyte and lymphoma cell surface protein that promotes intercellular adhesion. We have previously shown that the invasion of hepatocyte cultures by lymphoma cells is inhibited by anti-LFA-1 antibodies (Roos, E., and F. F. Roossien. 1987. J. Cell Biol. 105:553-559). In addition, we now report that LFA-1 is also involved in invasion of lymphoma cells into fibroblast monolayers. To investigate the role of LFA-1 in metastasis of these lymphoma cells, we have generated mutants that are deficient in LFA-1 cell surface expression because of impaired synthesis of either the alpha or beta subunit precursor of LFA-1. We identified at least three distinct mutant clones. The invasive potential of the mutant cells in vitro, in both hepatocyte and fibroblast cultures, was considerably lower than that of parental cells. The metastatic potential of the mutants was much reduced, indicating that LFA-1 expression is required for efficient metastasis formation by certain lymphoma cells.

Download Full-text

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Journal of Biological Chemistry ◽

10.1074/jbc.m109.055608 ◽

2010 ◽

Vol 285 (27) ◽

pp. 20664-20674 ◽

Cited By ~ 39

Author(s):

Sylvia Ullrich ◽

Anna Münch ◽

Stephanie Neumann ◽

Elisabeth Kremmer ◽

Jörg Tatzelt ◽

...

Keyword(s):

Membrane Protein ◽

Cell Surface ◽

Amyloid Precursor Protein ◽

Surface Expression ◽

Precursor Protein ◽

Cell Surface Expression ◽

The Novel

Download Full-text

Implications of cell surface expression of the Alzheimer's beta-amyloid precursor protein

Neurobiology of Aging ◽

10.1016/s0197-4580(00)82595-6 ◽

2000 ◽

Vol 21 ◽

pp. 82-83

Author(s):

Sonia S. Jung ◽

Neil R. Cashman

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

Beta Amyloid ◽

Surface Expression ◽

Precursor Protein ◽

Cell Surface Expression

Download Full-text

Secreted Amyloid Precursor Protein-Alpha Enhances LTP Through the Synthesis and Trafficking of Ca2+-Permeable AMPA Receptors

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.660208 ◽

2021 ◽

Vol 14 ◽

Author(s):

Rhys W. Livingstone ◽

Megan K. Elder ◽

Anurag Singh ◽

Courteney M. Westlake ◽

Warren P. Tate ◽

...

Keyword(s):

Cell Surface ◽

Amyloid Precursor Protein ◽

De Novo ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Surface Expression ◽

Receptor Expression ◽

Precursor Protein ◽

Cell Surface Expression ◽

Proximity Ligation Assay

Regulation of AMPA receptor expression by neuronal activity and neuromodulators is critical to the expression of both long-term potentiation (LTP) and memory. In particular, Ca2+-permeable AMPARs (CP-AMPAR) play a unique role in these processes due to their transient, activity-regulated expression at synapses. Secreted amyloid precursor protein-alpha (sAPPα), a metabolite of the parent amyloid precursor protein (APP) has been previously shown to enhance hippocampal LTP as well as memory formation in both normal animals and in Alzheimer’s disease models. In earlier work we showed that sAPPα promotes trafficking of GluA1-containing AMPARs to the cell surface and specifically enhances synthesis of GluA1. To date it is not known whether de novo synthesized GluA1 form CP-AMPARs or how they contribute to sAPPα-mediated plasticity. Here, using fluorescent non-canonical amino acid tagging–proximity ligation assay (FUNCAT-PLA), we show that brief treatment of primary rat hippocampal neurons with sAPPα (1 nM, 30 min) rapidly enhanced the cell-surface expression of de novo GluA1 homomers and reduced levels of de novo GluA2, as well as extant GluA2/3-AMPARs. The de novo GluA1-containing AMPARs were localized to extrasynaptic sites and later internalized by sAPPα-driven expression of the activity-regulated cytoskeletal-associated protein, Arc. Interestingly, longer exposure to sAPPα increased synaptic levels of GluA1/2 AMPARs. Moreover, the sAPPα-mediated enhancement of LTP in area CA1 of acute hippocampal slices was dependent on CP-AMPARs. Together, these findings show that sAPPα engages mechanisms which specifically enhance the synthesis and cell-surface expression of GluA1 homomers, underpinning the sAPPα-driven enhancement of synaptic plasticity in the hippocampus.

Download Full-text