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14-3-3? binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:G?i-AlF4- signaling complex and RGS14 nuclear localization.

ABSTRACT: Regulator of G protein signaling 14 (RGS14) is a multifunctional brain scaffolding protein that integrates G protein and Ras/ERK signaling pathways. It is also a nucleocytoplasmic shuttling protein. RGS14 binds active G?i/o via its RGS domain, Raf and active H-Ras-GTP via its R1 Ras-binding domain (RBD), and inactive G?i1/3 via its G protein regulatory (GPR) domain. RGS14 suppresses long-term potentiation (LTP) in the CA2 region of the hippocampus, thereby regulating hippocampally based learning and memory. The 14-3-3 family of proteins is necessary for hippocampal LTP and associative learning and memory. Here, we show direct interaction between RGS14 and 14-3-3? at two distinct sties, one phosphorylation-independent and the other phosphorylation-dependent at Ser-218 that is markedly potentiated by signaling downstream of active H-Ras. Using bioluminescence resonance energy transfer (BRET), we show that the pSer-218-dependent RGS14/14-3-3? interaction inhibits active G?i1-AlF4- binding to the RGS domain of RGS14 but has no effect on active H-Ras and inactive G?i1-GDP binding to RGS14. By contrast, the phosphorylation-independent binding of 14-3-3 has no effect on RGS14/G?i interactions but, instead, inhibits (directly or indirectly) RGS14 nuclear import and nucleocytoplasmic shuttling. Together, our findings describe a novel mechanism of negative regulation of RGS14 functions, specifically interactions with active G?i and nuclear import, while leaving the function of other RGS14 domains intact. Ongoing studies will further elucidate the physiological function of this interaction between RGS14 and 14-3-3?, providing insight into the functions of both RGS14 and 14-3-3 in their roles in modulating synaptic plasticity in the hippocampus.

SUBMITTER: Gerber KJ

PROVIDER: S-EPMC6153293 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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14-3-3γ binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:Gαi-AlF4- signaling complex and RGS14 nuclear localization.

Gerber Kyle J KJ Squires Katherine E KE Hepler John R JR

The Journal of biological chemistry 20180809 38

Regulator of G protein signaling 14 (RGS14) is a multifunctional brain scaffolding protein that integrates G protein and Ras/ERK signaling pathways. It is also a nucleocytoplasmic shuttling protein. RGS14 binds active Gαi/o via its RGS domain, Raf and active H-Ras-GTP via its R1 Ras-binding domain (RBD), and inactive Gαi1/3 via its G protein regulatory (GPR) domain. RGS14 suppresses long-term potentiation (LTP) in the CA2 region of the hippocampus, thereby regulating hippoc ...[more]

PMID: 30093406

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Project description:Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell-cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.

Dataset Information

14-3-3? binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:G?i-AlF4- signaling complex and RGS14 nuclear localization.

Publications

14-3-3γ binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:Gα<sub>i</sub>-AlF<sub>4</sub><sup>-</sup> signaling complex and RGS14 nuclear localization.

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