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Fontana, Jacopo M.
Publications (6 of 6) Show all publications
Panizza, E., Zhang, L., Fontana, J. M., Hamada, K., Svensson, D., Akkuratov, E. E., . . . Aperia, A. (2019). Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival. The FASEB Journal, 33(9), 10193-10206
Open this publication in new window or tab >>Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 9, p. 10193-10206Article in journal (Refereed) Published
Abstract [en]

The ion pump Na+, K+-ATPase (NKA) is a receptor for the cardiotonic steroid ouabain. Subsaturating concentration of ouabain triggers intracellular calcium oscillations, stimulates cell proliferation and adhesion, and protects from apoptosis. However, it is controversial whether ouabain-bound NKA is considered a signal transducer. To address this question, we performed a global analysis of protein phosphorylation in COS-7 cells, identifying 2580 regulated phosphorylation events on 1242 proteins upon 10- and 20-min treatment with ouabain. Regulated phosphorylated proteins include the inositol triphosphate receptor and stromal interaction molecule, which are essential for initiating calcium oscillations. Hierarchical clustering revealed that ouabain triggers a structured phosphorylation response that occurs in a well-defined, time-dependent manner and affects specific cellular processes, including cell proliferation and cell-cell junctions. We additionally identify regulation of the phosphorylation of several calcium and calmodulin-dependent protein kinases (CAMKs), including 2 sites of CAMK type II-gamma (CAMK2G), a protein known to regulate apoptosis. To verify the significance of this result, CAMK2G was knocked down in primary kidney cells. CAMK2G knockdown impaired ouabain-dependent protection from apoptosis upon treatment with high glucose or serum deprivation. In conclusion, we establish NKA as the coordinator of a broad, tightly regulated phosphorylation response in cells and define CAMK2G as a downstream effector of NKA.-Panizza, E., Zhang, L., Fontana, J. M., Hamada, K., Svensson, D., Akkuratov, E. E., Scott, L., Mikoshiba, K., Brismar, H., Lehtio, J., Aperia, A. Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
calcium and calmodulin-dependent protein kinase, phosphoproteomics, apoptosis, inositol triphosphate receptor, kidney
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-259434 (URN)10.1096/fj.201900445R (DOI)000482214200038 ()31199885 (PubMedID)2-s2.0-85071786321 (Scopus ID)
Note

QC 20190924

Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Fontana, J. M., Khodus, G. R., Unnersjö Jess, D., Blom, H., Aperia, A. & Brismar, H. (2019). Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney. The FASEB Journal, 33(3), 4089-4096
Open this publication in new window or tab >>Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 3, p. 4089-4096Article in journal (Refereed) Published
Abstract [en]

The central role of calcium signaling during development of early vertebrates is well documented, but little is known about its role in mammalian embryogenesis. We have used immunofluorescence and time-lapse calcium imaging of cultured explanted embryonic rat kidneys to study the role of calcium signaling for branching morphogenesis. In mesenchymal cells, we recorded spontaneous calcium activity that was characterized by irregular calcium transients. The calcium signals were dependent on release of calcium from intracellular stores in the endoplasmic reticulum. Down-regulation of the calcium activity, both by blocking the sarco-endoplasmic reticulum Ca2+-ATPase and by chelating cytosolic calcium, resulted in retardation of branching morphogenesis and a reduced formation of primitive nephrons but had no effect on cell proliferation. We propose that spontaneous calcium activity contributes with a stochastic factor to the self-organizing process that controls branching morphogenesis, a major determinant of the ultimate number of nephrons in the kidney.Fontana, J. M., Khodus, G. R., Unnersjo-Jess, D., Blom, H., Aperia, A., Brismar, H. Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
organogenesis, nephron, calcium imaging
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-246250 (URN)10.1096/fj.201802054R (DOI)000459794800079 ()30496703 (PubMedID)
Note

QC 20190402

Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02Bibliographically approved
Bernhem, K., Zhang, L., Fontana, J. M., Nilsson, L., Scott, L., Brismar, H. & Aperia, A. (2017). Mapping the apoptotic process with super resolution microscopy in kidney cells challenged with high glucose. Paper presented at Annual Meeting of the American-Society-for-Pharmacology-and-Experimental-Therapeutics (ASPET) at Experimental Biology Meeting, APR 22-26, 2017, Chicago, IL. The FASEB Journal, 31
Open this publication in new window or tab >>Mapping the apoptotic process with super resolution microscopy in kidney cells challenged with high glucose
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2017 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-214903 (URN)000405986502532 ()
Conference
Annual Meeting of the American-Society-for-Pharmacology-and-Experimental-Therapeutics (ASPET) at Experimental Biology Meeting, APR 22-26, 2017, Chicago, IL
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171023

Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2018-02-21Bibliographically approved
Yin, H., Fontana, J. M., Solandt, J., Jussi, J. I., Xu, H., Brismar, H. & Fu, Y. (2017). Quantum dots modulate intracellular Ca2+ level in lung epithelial cells. International Journal of Nanomedicine, 12, 2781-2792
Open this publication in new window or tab >>Quantum dots modulate intracellular Ca2+ level in lung epithelial cells
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2017 (English)In: International Journal of Nanomedicine, ISSN 1176-9114, E-ISSN 1178-2013, Vol. 12, p. 2781-2792Article in journal (Refereed) Published
Abstract [en]

While adverse effects of nanoparticles on lung health have previously been proposed, few studies have addressed the direct effects of nanoparticle exposure on the airway epithelium. In this work, we examine the response of the pulmonary airway to nanoparticles by measuring intracellular Ca2+ concentration ([Ca2+](i)) in the Calu-3 epithelial layer stimulated by 3-mercaptopropionic-acid (3MPA) coated CdSe-CdS/ZnS core-multishell quantum dots (QDs). Simultaneous transient transepithelial electrical resistance (TEER) decrease and global [Ca2+](i) increase in Calu-3 epithelial layer, accompanied by cell displacements, contraction, and expansion, were observed under QD deposition. This suggests that a QD-induced global [Ca2+](i) increase in the Calu-3 epithelial layer caused the transient TEER decrease. The [Ca2+](i) increase was marked and rapid in the apical region, while [Ca2+](i) decreased in the basolateral region of the epithelial layer. TEER transient response and extracellular Ca2+ entry induced by QD deposition were completely inhibited in cells treated with stretched-activated (SA) inhibitor GdCl3 and store-operated calcium entry (SOCE) inhibitor BTP2 and in cells immersed in Ca2+-free medium. The voltage-gated calcium channel (VGCC) inhibitor nifedipine decreased, stabilized, and suppressed the TEER response, but did not affect the [Ca2+](i) increase, due to QD deposition. This demonstrates that the Ca2+ influx activated by QDs' mechanical stretch occurs through activation of both SA and SOCE channels. QD-induced [Ca2+](i) increase occurred in the Calu-3 epithelial layer after culturing for 15 days, while significant TEER drop only occurred after 23 days. This work provides a new perspective from which to study direct interactions between airway epithelium and nanoparticles and may help to reveal the pathologies of pulmonary disease.

Place, publisher, year, edition, pages
DOVE MEDICAL PRESS LTD, 2017
Keywords
Calu-3 epithelial layer, quantum dot, intracellular Ca2+ concentration [Ca2+](i), transepithelial electrical resistance, cell movement
National Category
Nano Technology Pharmaceutical Sciences
Identifiers
urn:nbn:se:kth:diva-206308 (URN)10.2147/IJN.S130136 (DOI)000398663200001 ()2-s2.0-85017256402 (Scopus ID)
Note

QC 20170505

Available from: 2017-05-05 Created: 2017-05-05 Last updated: 2019-10-20Bibliographically approved
Fontana, J. M., Jess, D. U., Blom, H., Brismar, H. & Aperia, A. (2016). Role of calcium signaling for GDNF secretion, ureter branching and early nephron formation. Paper presented at Experimental Biology Meeting, APR 02-06, 2016, San Diego, CA. The FASEB Journal, 30
Open this publication in new window or tab >>Role of calcium signaling for GDNF secretion, ureter branching and early nephron formation
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2016 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 30Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-242657 (URN)000406444705388 ()
Conference
Experimental Biology Meeting, APR 02-06, 2016, San Diego, CA
Note

QC 201902255

Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Fontana, J. M., Bernhem, K., Zhang, L., Nilsson, L., Blom, H., Brismar, H. & Aperia, A. (2015). Ouabain, a Na, K-ATPase ligand, intervenes with the onset of glucose-triggered apoptosis. Molecular Biology of the Cell, 26
Open this publication in new window or tab >>Ouabain, a Na, K-ATPase ligand, intervenes with the onset of glucose-triggered apoptosis
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2015 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 26Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
AMER SOC CELL BIOLOGY, 2015
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-242778 (URN)000209928500656 ()
Note

QC 20190211

Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved
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