期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 28, 期 3, 页码 837-851出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2016040414
关键词
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资金
- Swedish Research Council
- Swedish Governmental Agency for Innovation Systems
- Swiss National Science Foundation [P3SMP3_151739]
- National Institutes of Health [DK057683, DK062472, DK091218]
- NIH [DK083511, DK093746, DK095045]
Tyrosine and serine/threonine signal-transduction pathways influence many aspects of cell behavior, including the spatial and temporal regulation of the actin cytoskeleton. However, little is known about how input from diverse tyrosine and serine/threonine kinases is integrated to control Rho protein crosstalk and actin remodeling, which are critically important in podocyte health and disease. Here we unveil the proteolytically-regulated, actin organizing protein synaptopodin as a coincidence detector of tyrosine versus serine/threonine phosphorylation. We show that serine/threonine and tyrosine kinases duel for synaptopodin stability versus degradation. EGFR/Src-mediated tyrosine phosphorylation of synaptopodin in podocytes promotes binding to the serine/threonine phosphatase calcineurin. This leads to the loss of 14-3-3 binding, resulting in synaptopodin degradation, Vav2 activation, enhanced Rac1 signaling, and ultimate loss of stress fibers. Our studies reveal how synaptopodin, a single proteolytically-controlled protein, integrates antagonistic tyrosine versus serine/threonine phosphorylation events for the dynamic control of the actin cytoskeleton in podocytes.
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