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Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation.

ABSTRACT: Nik-related kinase (Nrk) is a Ser/Thr kinase and was initially discovered as a molecule that was predominantly detected in skeletal muscles during development. A recent study using Nrk-null mice suggested the importance of Nrk in proper placental development; however, the molecular mechanism remains unknown. In this study, we demonstrated that differentiated trophoblasts from murine embryonic stem cells (ESCs) endogenously expressed Nrk and that Nrk disruption led to the enhanced proliferation of differentiated trophoblasts. This phenomenon may reflect the overproliferation of trophoblasts that has been reported in enlarged placentas of Nrk-null mice. Furthermore, we demonstrated that AKT phosphorylation at Ser473 was upregulated in Nrk-null trophoblasts and that inhibition of AKT phosphorylation cancelled the enhanced proliferation observed in differentiated Nrk-null trophoblasts. These results indicated that the upregulation of AKT phosphorylation was the possible cause of enhanced proliferation observed in Nrk-null trophoblasts. The upregulation of AKT phosphorylation was also confirmed in enlarged Nrk-null placentas in vivo, suggesting that proper regulation of AKT by Nrk was important for normal placental development. In addition, our detailed analysis on phosphorylation status of AKT isoforms in newly established trophoblast stem cells (TSCs) revealed that different levels of upregulation of AKT phosphorylation were occurred in Nrk-null TSCs depending on AKT isoforms. These results further support the importance of Nrk in proper development of trophoblast lineage cells and indicate the possible application of TSCs for the analysis of differently regulated activation mechanisms of AKT isoforms.

SUBMITTER: Morioka Y

PROVIDER: S-EPMC5289614 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation.

Morioka Yuka Y Nam Jin-Min JM Ohashi Takashi T

PloS one 20170202 2

Nik-related kinase (Nrk) is a Ser/Thr kinase and was initially discovered as a molecule that was predominantly detected in skeletal muscles during development. A recent study using Nrk-null mice suggested the importance of Nrk in proper placental development; however, the molecular mechanism remains unknown. In this study, we demonstrated that differentiated trophoblasts from murine embryonic stem cells (ESCs) endogenously expressed Nrk and that Nrk disruption led to the enhanced proliferation o ...[more]

PMID: 28152035

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Project description:Receptor for activated protein kinase C1 (RACK1) is an intracellular scaffolding protein known to interact with the inositol-1,4,5-trisphosphate receptor and thereby enhance calcium release from the sarcoplasmic reticulum. Because calcium signaling may affect vascular smooth muscle cell proliferation, we investigated whether RACK1 regulates proliferation of rat preglomerular microvascular smooth muscle cells. Western blot analysis indicated that preglomerular microvascular smooth muscle cells robustly express RACK1 protein, and coimmunoprecipitation experiments demonstrated that RACK1 binds the inositol-1,4,5-trisphosphate receptor. RACK1 small interfering RNA (siRNA) decreased RACK1 mRNA and protein expression, significantly (P=0.0225) reduced steady-state basal levels of intracellular calcium (6712±156 versus 7408±248, arbitrary fluorescence units in RACK1 siRNA-treated versus control cells, respectively) and significantly (P<0.0001) decreased cell proliferation by ?50%. Xestospongin C and 2-aminoethoxydiphenyl borate (antagonists of inositol-1,4,5-trisphosphate receptors), cyclopiazonic acid (sarcoplasmic reticulum Ca(2+)-ATPase inhibitor), and calmidazolium (calmodulin inhibitor) mimicked the effects of RACK1 siRNA on proliferation, and RACK1 siRNA had no additional effects on proliferation in the presence of these agents. RACK1 siRNA did not affect the expression of cyclin D1/2 or phosphorylation of retinoblastoma protein (progrowth cell cycle regulators), yet it caused compensatory decreases in the expression of p21(Cip1/Waf1) and p27(Kip1) (antigrowth cell cycle regulators). Like preglomerular microvascular smooth muscle cells, glomerular mesangial cells also expressed high levels of RACK1, and RACK1 siRNA inhibited their proliferation. In conclusion, RACK1 modulates proliferation of preglomerular microvascular smooth muscle cells and glomerular mesangial cells, likely via the inositol-1,4,5-trisphosphate receptor/calcium/calmodulin pathway. RACK1 may represent a novel druggable target for treating renal diseases, such as glomerulosclerosis.

Dataset Information

Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation.

Publications

Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation.

Similar Datasets

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