Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

Rao, Jia; Ashraf, Shazia; Tan, Weizhen; Ven, Amelie T. van der; Gee, Heon Yung; Braun, Daniela A.; Fehér, Krisztina; George, Sudeep P.; Esmaeilniakooshkghazi, Amin; Choi, Won‐Il; Jobst-Schwan, Tilman; Schneider, Ronen; Schmidt, Johanna Magdalena; Widmeier, Eugen; Warejko, Jillian K.; Hermle, Tobias; Schapiro, David; Lovric, Svjetlana; Shril, Shirlee; Daga, Ankana; Nayır, Ahmet; Shenoy, Mohan; Tse, Yincent; Bald, Martin; Helmchen, U.; Mır, Sevgı; Berdeli, Afig; Kari, Jameela A.; Desoky, Sherif El; Soliman, Neveen A.; Bagga, Arvind; Mane, Shrikant; Jairajpuri, Mohamad Aman; Lifton, Richard P.; Khurana, Seema; Martins, José; Hildebrandt, Friedhelm

doi:10.1172/jci94138

Cited by 40 publications

(44 citation statements)

References 56 publications

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“…4a, b). This result is consistent with the findings of Rao et al 5 . In addition, the Boyden chamber assay using the xCELLigence system showed that the knockdown of PLCE1 resulted in a decreased migratory phenotype in cultured podocytes (Fig.…”

Section: Loss Of Plce1 Resulted In Decreased Active Rac1 and Cdc42 Ansupporting

confidence: 94%

“…A significant proportion of steroid-resistant nephrotic syndromes (SRNSs) have a genetic background and result from a single-gene defect. The genetic heterogeneity of SRNS can be demonstrated by the fact that mutations in approximately 50 genes have been identified to be capable of causing SRNS 4,5 . Research on the function of genes linked to SRNS has revealed that podocytes are critical sites for the pathogenesis of SRNS 6,7 .…”

Section: Introductionmentioning

confidence: 99%

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PLCE1 regulates the migration, proliferation, and differentiation of podocytes

Choi

et al. 2020

Exp Mol Med

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PLCE1 encodes phospholipase C epsilon, and its mutations cause recessive nephrotic syndrome. However, the mechanisms by which PLCE1 mutations result in defects associated with glomerular function are not clear. To address this, we investigated the function of PLCE1 in podocytes called glomerular epithelial cells, where the pathogenesis of nephrotic syndrome converges. PLCE1 colocalized with Rho GTPases in glomeruli. Further, it interacted with Rho GTPases through the pleckstrin homology domain and Ras GTP-binding domains 1/2. Knockdown or knockout of PLCE1 in podocytes resulted in decreased levels of GTP-bound Rac1 and Cdc42, but not those of RhoA, and caused a reduction in cell migration. PLCE1 interacted with NCK2 but not with NCK1. Similar to the PLCE1 knockout, NCK2 knockout resulted in decreased podocyte migration. Knockout of PLCE1 reduced the EGF-induced activation of ERK and cell proliferation in podocytes, whereas knockout of NCK2 did not affect proliferation. Further, the knockout of PLCE1 also resulted in decreased expression of podocyte markers, including NEPH1, NPHS1, WT1, and SYNPO, upon differentiation, but the knockout of NCK2 did not affect the expression of these markers. Therefore, our findings demonstrate that PLCE1 regulates Rho GTPase activity and cell migration through interacting with NCK2 and that PLCE1 also plays a role in the proliferation and differentiation of podocytes, regardless of the presence of NCK2.

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Section: Loss Of Plce1 Resulted In Decreased Active Rac1 and Cdc42 Ansupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

PLCE1 regulates the migration, proliferation, and differentiation of podocytes

Choi

et al. 2020

Exp Mol Med

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“…Advillin is 75% homologous to villin, and 65% homologous to gelsolin and adseverin. Recently, AVIL mutants were found to be involved in the alteration PLCE1 action, and contribute to the Steroid-resistant nephrotic syndrome 55 . Even though there are studies suggesting connections between these actin-regulatory proteins and cancer 56,57 , no direct evidence has shown any of the family members to be oncogenic, or tumor suppressive.…”

Section: Discussionmentioning

confidence: 99%

A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma

et al. 2020

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Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain. Glioma patients with increased AVIL expression have a worse prognosis. Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells. Conversely, overexpressing AVIL promoted cell proliferation and migration, enabled fibroblasts to escape contact inhibition, and transformed immortalized astrocytes, supporting AVIL being a bona fide oncogene. We provide evidence that the tumorigenic effect of AVIL is partly mediated by FOXM1, which regulates LIN28B, whose expression also correlates with clinical prognosis. AVIL regulates the cytoskeleton through modulating F-actin, while mutants disrupting F-actin binding are defective in its tumorigenic capabilities.

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“…The evaluation of podocyte migration rate is an established functional assay in podocyte cell lines and has been extensively used to characterize the deleteriousness of monogenic mutations in SRNS genes. 2,7,14,22,24,32,38 To analyze the role of GAPVD1, we generated stable shRNA-expressing human Mock-GFP, precipitates Myc-tagged nephrin, yielding only the lower of two bands (arrow head). (B) GAPVD1 cDNA constructs that reflect the mutations from patients A4619 (p.Leu414Val) and B1391 (p.Arg937Gln) exhibit reduced binding affinity to nephrin.…”

Section: Analysis Of Podocyte Migration Rate Indicates Functional Sigmentioning

confidence: 99%