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Title: Effect of TGFβ on calcium signaling in megakaryocytes

Abstract

TGFβ is a powerful regulator of megakaryocyte maturation and platelet formation. As previously shown for other cell types, TGFβ may up-regulate the expression of the serum & glucocorticoid inducible kinase SGK1, an effect requiring p38 kinase. SGK1 has in turn recently been shown to participate in the regulation of cytosolic Ca{sup 2+} activity ([Ca{sup 2+}]{sub i}) in megakaryocytes and platelets. SGK1 phosphorylates the IκB kinase (IKKα/β), which in turn phosphorylates the inhibitor protein IκBα resulting in nuclear translocation of nuclear factor NFκB. Genes up-regulated by NFκB include Orai1, the pore forming ion channel subunit accomplishing store operated Ca{sup 2+} entry (SOCE). The present study explored whether TGFβ influences Ca{sup 2+} signaling in megakaryocytes. [Ca{sup 2+}]{sub i} was determined by Fura-2 fluorescence and SOCE from the increase of [Ca{sup 2+}]{sub i} following re-addition of extracellular Ca{sup 2+} after store depletion by removal of extracellular Ca{sup 2+} and inhibition of the sarcoendoplasmatic Ca{sup 2+} ATPase (SERCA) with thapsigargin (1 μM). As a result, TGFβ (60 ng, 24 h) increased SOCE, an effect significantly blunted by p38 kinase inhibitor Skepinone-L (1 μM), SGK1 inhibitor EMD638683 (50 μM) and NFκB inhibitor wogonin (100 μM). In conclusion, TGFβ is a powerful regulator of store operated Ca{sup 2+} entry into megakaryocytes, anmore » effect mediated by a signaling cascade involving p38 kinase, SGK1 and NFκB. - Highlights: • TGFβ up-regulates store operated Ca{sup 2+} entry (SOCE) in megakaryocytes. • The effect of TGFβ on SOCE is blunted by p38 kinase inhibitor Skepinone-L. • The effect of TGFβ on SOCE is virtually abrogated by SGK1 inhibitor EMD638683. • The effect of TGFβ on SOCE is almost abolished by NFκB inhibitor wogonin. • The effect of TGFβ is expected to enhance sensitivity of platelets to activation.« less

Authors:
 [1];  [1];  [2]; ;  [1];  [1];  [2];  [3];  [4];  [1]
  1. Department of Physiology I, University of Tübingen, Tübingen (Germany)
  2. (Germany)
  3. Department of Pharmacy, University of Tübingen, Tübingen (Germany)
  4. Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Tübingen (Germany)
Publication Date:
OSTI Identifier:
22462051
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 461; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BONE MARROW CELLS; CALCIUM; CALCIUM IONS; FLUORESCENCE; GENES; GLUCOCORTICOIDS; INHIBITION; PROTEINS; SENSITIVITY; SIGNALS

Citation Formats

Yan, Jing, Schmid, Evi, Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Almilaji, Ahmad, Shumilina, Ekaterina, Borst, Oliver, Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Tübingen, Laufer, Stefan, Gawaz, Meinrad, and Lang, Florian, E-mail: florian.lang@uni-tuebingen.de. Effect of TGFβ on calcium signaling in megakaryocytes. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.03.159.
Yan, Jing, Schmid, Evi, Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Almilaji, Ahmad, Shumilina, Ekaterina, Borst, Oliver, Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Tübingen, Laufer, Stefan, Gawaz, Meinrad, & Lang, Florian, E-mail: florian.lang@uni-tuebingen.de. Effect of TGFβ on calcium signaling in megakaryocytes. United States. doi:10.1016/J.BBRC.2015.03.159.
Yan, Jing, Schmid, Evi, Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Almilaji, Ahmad, Shumilina, Ekaterina, Borst, Oliver, Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Tübingen, Laufer, Stefan, Gawaz, Meinrad, and Lang, Florian, E-mail: florian.lang@uni-tuebingen.de. Fri . "Effect of TGFβ on calcium signaling in megakaryocytes". United States. doi:10.1016/J.BBRC.2015.03.159.
@article{osti_22462051,
title = {Effect of TGFβ on calcium signaling in megakaryocytes},
author = {Yan, Jing and Schmid, Evi and Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen and Almilaji, Ahmad and Shumilina, Ekaterina and Borst, Oliver and Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Tübingen and Laufer, Stefan and Gawaz, Meinrad and Lang, Florian, E-mail: florian.lang@uni-tuebingen.de},
abstractNote = {TGFβ is a powerful regulator of megakaryocyte maturation and platelet formation. As previously shown for other cell types, TGFβ may up-regulate the expression of the serum & glucocorticoid inducible kinase SGK1, an effect requiring p38 kinase. SGK1 has in turn recently been shown to participate in the regulation of cytosolic Ca{sup 2+} activity ([Ca{sup 2+}]{sub i}) in megakaryocytes and platelets. SGK1 phosphorylates the IκB kinase (IKKα/β), which in turn phosphorylates the inhibitor protein IκBα resulting in nuclear translocation of nuclear factor NFκB. Genes up-regulated by NFκB include Orai1, the pore forming ion channel subunit accomplishing store operated Ca{sup 2+} entry (SOCE). The present study explored whether TGFβ influences Ca{sup 2+} signaling in megakaryocytes. [Ca{sup 2+}]{sub i} was determined by Fura-2 fluorescence and SOCE from the increase of [Ca{sup 2+}]{sub i} following re-addition of extracellular Ca{sup 2+} after store depletion by removal of extracellular Ca{sup 2+} and inhibition of the sarcoendoplasmatic Ca{sup 2+} ATPase (SERCA) with thapsigargin (1 μM). As a result, TGFβ (60 ng, 24 h) increased SOCE, an effect significantly blunted by p38 kinase inhibitor Skepinone-L (1 μM), SGK1 inhibitor EMD638683 (50 μM) and NFκB inhibitor wogonin (100 μM). In conclusion, TGFβ is a powerful regulator of store operated Ca{sup 2+} entry into megakaryocytes, an effect mediated by a signaling cascade involving p38 kinase, SGK1 and NFκB. - Highlights: • TGFβ up-regulates store operated Ca{sup 2+} entry (SOCE) in megakaryocytes. • The effect of TGFβ on SOCE is blunted by p38 kinase inhibitor Skepinone-L. • The effect of TGFβ on SOCE is virtually abrogated by SGK1 inhibitor EMD638683. • The effect of TGFβ on SOCE is almost abolished by NFκB inhibitor wogonin. • The effect of TGFβ is expected to enhance sensitivity of platelets to activation.},
doi = {10.1016/J.BBRC.2015.03.159},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 461,
place = {United States},
year = {2015},
month = {5}
}