anoctamin 6
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2021 ◽  
Vol 22 (5) ◽  
pp. 2730
Author(s):  
Jana Seidel ◽  
Sinje Leitzke ◽  
Björn Ahrens ◽  
Maria Sperrhacke ◽  
Sucharit Bhakdi ◽  
...  

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137.



2021 ◽  
Vol 44 (2) ◽  
pp. 88-100
Author(s):  
Jae Won Roh ◽  
Ga Eun Hwang ◽  
Woo Kyung Kim ◽  
Joo Hyun Nam
Keyword(s):  


Platelets ◽  
2020 ◽  
pp. 1-9
Author(s):  
Delia I. Fernández ◽  
Marijke J. E. Kuijpers ◽  
Johan W. M. Heemskerk


Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 625 ◽  
Author(s):  
Jiraporn Ousingsawat ◽  
Rainer Schreiber ◽  
Karl Kunzelmann

Ca2+ activated Cl− channels (TMEM16A; ANO1) support cell proliferation and cancer growth. Expression of TMEM16A is strongly enhanced in different types of malignomas. In contrast, TMEM16F (ANO6) operates as a Ca2+ activated chloride/nonselective ion channel and scrambles membrane phospholipids to expose phosphatidylserine at the cell surface. Both phospholipid scrambling and cell swelling induced through activation of nonselective ion currents appear to destabilize the plasma membrane thereby causing cell death. There is growing evidence that activation of TMEM16F contributes to various forms of regulated cell death. In the present study, we demonstrate that ferroptotic cell death, occurring during peroxidation of plasma membrane phospholipids activates TMEM16F. Ferroptosis was induced by erastin, an inhibitor of the cystine-glutamate antiporter and RSL3, an inhibitor of glutathione peroxidase 4 (GPX4). Cell death was largely reduced in the intestinal epithelium, and in peritoneal macrophages isolated from mice with tissue-specific knockout of TMEM16F. We show that TMEM16F is activated during erastin and RSL3-induced ferroptosis. In contrast, inhibition of ferroptosis by ferrostatin-1 and by inhibitors of TMEM16F block TMEM16F currents and inhibit cell death. We conclude that activation of TMEM16F is a crucial component during ferroptotic cell death, a finding that may be useful to induce cell death in cancer cells.



2019 ◽  
Vol 11 (11) ◽  
pp. 979-993 ◽  
Author(s):  
Florian Bleibaum ◽  
Anselm Sommer ◽  
Martin Veit ◽  
Björn Rabe ◽  
Jörg Andrä ◽  
...  

Abstract Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer’s disease. The mechanisms underlying ADAM10 sheddase activation are incompletely understood. Here, we show that transient exposure of the negatively charged phospholipid phosphatidylserine (PS) is necessarily required. The soluble PS headgroup was found to act as competitive inhibitor of substrate cleavage. Overexpression of the Ca2+-dependent phospholipid scramblase Anoctamin-6 (ANO6) led to increased PS externalization and substrate release. Transfection with a constitutively active form of ANO6 resulted in maximum sheddase activity in the absence of any stimulus. Calcium-dependent ADAM10 activation could not be induced in lymphocytes of patients with Scott syndrome harbouring a missense mutation in ANO6. A putative PS-binding motif was identified in the conserved stalk region. Replacement of this motif resulted in strong reduction of sheddase activity. In conjunction with the recently described 3D structure of the ADAM10 extracellular domain, a model is advanced to explain how surface-exposed PS triggers ADAM10 sheddase function.



2018 ◽  
Vol 1865 (11) ◽  
pp. 1598-1610 ◽  
Author(s):  
Martin Veit ◽  
Katharina Isabelle Koyro ◽  
Björn Ahrens ◽  
Florian Bleibaum ◽  
Martin Munz ◽  
...  
Keyword(s):  


2018 ◽  
Author(s):  
Sarah E Stewart ◽  
Avraham Ashkenazi ◽  
Athena Williamson ◽  
David C Rubinsztein ◽  
Kevin Moreau

AbstractAnnexins are phospholipid binding proteins that somehow translocate from the inner leaflet of the plasma membrane to the outer leaflet. For example, Annexin A2 is known to localise to the outer leaflet of the plasma membrane (cell surface) where it is involved in plasminogen activation leading to fibrinolysis and cell migration, among other functions. Despite having well described extracellular functions, the mechanism of annexin transport from the cytoplasmic inner leaflet to the extracellular outer leaflet of the plasma membrane remains unclear. Here, we show that phospholipid flipping activity is crucial for the transport of annexins A2 and A5 across membranes in cells and in liposomes. We identified TMEM16F (anoctamin-6) as a lipid scramblase required for transport of these annexins to the outer leaflet of the plasma membrane. This work reveals a mechanism for annexin translocation across membranes which depends on plasma membrane phospholipid flipping.



2017 ◽  
Vol 470 (2) ◽  
pp. 305-314 ◽  
Author(s):  
Filipa Simões ◽  
Jiraporn Ousingsawat ◽  
Podchanart Wanitchakool ◽  
Ana Fonseca ◽  
Inês Cabrita ◽  
...  
Keyword(s):  


2017 ◽  
Vol 58 (1) ◽  
pp. 492 ◽  
Author(s):  
Juni Banerjee ◽  
Chi-Ting Leung ◽  
Ang Li ◽  
Kim Peterson-Yantorno ◽  
Huan Ouyang ◽  
...  


2016 ◽  
Vol 291 (52) ◽  
pp. 26816-26836 ◽  
Author(s):  
Joydeep Aoun ◽  
Mikio Hayashi ◽  
Irshad Ali Sheikh ◽  
Paramita Sarkar ◽  
Tultul Saha ◽  
...  


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