Dataset Information

Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes.

ABSTRACT: 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.

SUBMITTER: Buvall L

PROVIDER: S-EPMC5328162 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes.

Buvall Lisa L Wallentin Hanna H Sieber Jonas J Andreeva Svetlana S Choi Hoon Young HY Mundel Peter P Greka Anna A

Journal of the American Society of Nephrology : JASN 20160914 3

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 de ...[more]

PMID: 27628902

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Project description:The sulfoxidation of methionine residues within the phosphorylation motif of protein kinase substrates, may provide a mechanism to couple oxidative signals to changes in protein phosphorylation. Herein, we hypothesize that if the residues within a pair of phosphorylatable-sulfoxidable sites are functionally linked, then they might have been coevolving. To test this hypothesis a number of site pairs previously detected on human stress-related proteins has been subjected to analysis using eukaryote ortholog sequences and a phylogenetic approach.Overall, the results support the conclusion that in the eIF2? protein, serine phosphorylation at position 218 and methionine oxidation at position 222, belong to the same functional network. First, the observed data were much better fitted by Markovian models that assumed coevolution of both sites, with respect to their counterparts assuming independent evolution (p-value = 0.003). Second, this conclusion was robust with respect to the methods used to reconstruct the phylogenetic relationship between the 233 eukaryotic species analyzed. Third, the co-distribution of phosphorylatable and sulfoxidable residues at these positions showed multiple origins throughout the evolution of eukaryotes, which further supports the view of an adaptive value for this co-occurrence. Fourth, the possibility that the coevolution of these two sites might be due to structure-driven compensatory mutations was evaluated. The results suggested that factors other than those merely structural were behind the observed coevolution. Finally, the relationship detected between other modifiable site pairs from ataxin-2 (S814-M815), ataxin-2-like (S211-M215) and Pumilio homolog 1 (S124-M125), reinforce the view of a role for phosphorylation-sulfoxidation crosstalk.For the four stress-related proteins analyzed herein, their respective pairs of PTM sites (phosphorylatable serine and sulfoxidable methionine) were found to be evolving in a correlated fashion, which suggests a relevant role for methionine sulfoxidation and serine phosphorylation crosstalk in the control of protein translation under stress conditions.

Dataset Information

Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes.

Publications

Synaptopodin Is a Coincidence Detector of Tyrosine versus Serine/Threonine Phosphorylation for the Modulation of Rho Protein Crosstalk in Podocytes.

Similar Datasets

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