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Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival
Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, Solna, Sweden.;Cornell Univ, Ithaca, NY USA..
Karolinska Inst, Dept Womens & Childrens Hlth, Solna, Sweden..
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
RIKEN, Brain Sci Inst, Lab Dev Neurobiol, Saitama, Japan..
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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. Vol. 33, no 9, p. 10193-10206
Keywords [en]
calcium and calmodulin-dependent protein kinase, phosphoproteomics, apoptosis, inositol triphosphate receptor, kidney
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-259434DOI: 10.1096/fj.201900445RISI: 000482214200038PubMedID: 31199885Scopus ID: 2-s2.0-85071786321OAI: oai:DiVA.org:kth-259434DiVA, id: diva2:1353833
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QC 20190924

Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved

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Fontana, Jacopo M.Akkuratov, Evgeny E.Brismar, Hjalmar

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