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.

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…Synaptopodin protects the podocyte cytoskeleton in vitro and safeguards against filter barrier damage in mice by dynamically controlling the actin cytoskeleton in podocytes . Synaptopodin down‐regulation drives major actin cytoskeletal reorganization, foot process effacement and proteinuria development . In this study, F‐actin cytoskeletal disaggregation in siPlectin‐treated podocyte occurred in conjunction with p38 activation and synaptopodin down‐regulation.…”

“…35,56 Synaptopodin down-regulation drives major actin cytoskeletal reorganization, foot process effacement and proteinuria development. 57,58 In this study, F-actin cytoskeletal disaggregation in siPlectin-treated podocyte occurred in conjunction with p38 activation and synaptopodin down-regulation. Pretreating siPlectin-treated podocytes with a p38 inhibitor restored actin stress fibre integrity and synaptopodin expression to a pattern comparable with that observed in normal podocytes.…”

A Review of Podocyte Biology

“…Synaptopodin is essential for the integrity of the podocyte actin cytoskeleton and for the regulation of podocyte cell migration and regulates podocyte actin dynamics and migration by modulating RhoA signaling [31]. Epidermal growth factor receptor/Src-mediated phosphorylation of synaptopodin in podocytes stimulates binding to calcineurin, which results in synaptopodin degradation and enhanced Rac1 signaling, leading to the loss of actin stress fibers [32]. Rac1-GAP, which is associated with proteinuric kidney disease, increases when RhoA levels decrease.…”

A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

“…Rac1 activation leads to increased production of reactive oxygen species (ROS) (23,24). To establish a mechanistic understanding for the effects of AC1903 on the Rac1-TRPC5 pathway in podocytes, we measured ROS levels in vitro in podocytes treated with AngII (Fig.…”