Pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) leads to the activation of RhoGTPases promoting the malignant phenotypes of thyroid cancer

Yuan, Qingling; Fan, Yuxia; Liu, Zheng; Wang, Xiaoming; Jia, Meng; Dong, Yongqiang; Geng, Zushi; Zheng, Jian; Lu, Xiubo

doi:10.1007/s10495-023-01861-1

Cited by 4 publications

(4 citation statements)

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“…7B-C). Both genes encode guanine nucleotide exchange factors (GEFs) implicated in regulating cytoskeleton dynamics at the Golgi apparatus (38,39). Since alterations in trafficking are likely to induce stronger changes in lysosomal rather than total GCase activity, we assessed the effect of CRISPRa of PLEKHG4 and PLEKHG4B on lysosomal GCase activity using LysoFQ-GBA.…”

Section: Plekhg4 and Plekhg4b May Mediate The Downstream Effects Of O...mentioning

confidence: 99%

“…Indeed, CRISPRa of PLEKHG4, PLEKHG4B, and PLEKHG4+PLEKHG4B demonstrated a stronger effect on lysosomal GCase activity (assessed with LysoFQ-GBA) than on total cellular GCase activity (assessed with 4MU-Glc) in both LN-229 WT and LN-229 L444P cells. Since PLEKHG4 and PLEKHG4B are guanine nucleotide exchange factors (GEFs) implicated in cytoskeleton dynamics at the Golgi apparatus, their overexpression may enhance GCase trafficking and lysosomal GCase activity (38,39).…”

Section: Onecut2 Is a Posttranscriptional Regulator Of Gcase Activitymentioning

confidence: 99%

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Direct and indirect regulation of β-glucocerebrosidase by the transcription factorsUSF2andONECUT2

Ging,

Frick,

Schlachetzki

et al. 2024

Preprint

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Mutations in the GBA gene, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are the most prevalent genetic susceptibility factor for Parkinson's disease (PD). However, only approximately 20% of carriers develop the disease, suggesting the presence of genetic modifiers influencing the risk of developing PD in the presence of GBA mutations. Here we screened 1,634 human transcription factors (TFs) for their effect on GCase activity in cell lysates of the human glioblastoma line LN-229, into which we introduced the pathogenic GBA L444P variant via adenine base editing. Using a novel arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. Conversely, ablating USF2 increased GBA mRNA and led to enhanced levels of GCase protein and activity. While MITF, TFEC, and USF2 affected GBA transcription, ONECUT2 was found to control GCase trafficking by modulating the guanine exchange factors PLEKHG4 and PLEKHG4B. Hence, our study provides a systematic approach to identifying modulators of GCase activity, expands the transcriptional landscape of GBA regulation, and deepens our understanding of the mechanisms involved in influencing GCase activity.

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Section: Plekhg4 and Plekhg4b May Mediate The Downstream Effects Of O...mentioning

confidence: 99%

Section: Onecut2 Is a Posttranscriptional Regulator Of Gcase Activitymentioning

confidence: 99%

Direct and indirect regulation of β-glucocerebrosidase by the transcription factorsUSF2andONECUT2

Ging,

Frick,

Schlachetzki

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Ras homologue family member A (RhoA) is a member of the Rho family of GTPases that regulate cytoskeletal organization, gene expression, and transformation. − Ras superfamily members have been implicated in several human cancers. − The Rho GTPases include RhoA, Rac1, and Cdc42. Cdc42 controls filopodia formation.…”

Section: Introductionmentioning

confidence: 99%

“…Filopodia are actin–rich fingers that establish the direction of motility. Rac1 controls lamellipodia formation–actin–rich ruffles at the leading edge of the cell that initiate motion, and Rho controls the establishment of stress fibers whose formation results in the contractile force that moves the body of the cell behind the leading edge. − The G-protein coupled receptor (GPCR)-activated α subunits of G12/G13 (Gα 12 /Gα 13 ) interact with the regulator of G protein signaling (RGS) homology Rho guanine nucleotide exchange factor (RH-RhoGEF), thereby regulating the actin cytoskeleton. , The G12/13-RH-RhoGEF signaling mechanism is well conserved over species and is involved in critical steps for cell physiology and disease conditions, including embryonic development, oncogenesis, and cancer metastasis. , RhoA signaling has been shown to also be involved in neurodevelopmental disorders, neurodegenerative diseases, and traumatic brain injuries. − Ras proteins have been considered “undruggable” for over 30 years . Recent progress has discovered new ways to inhibit the activation mechanism of RhoA as well.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

Haspel,

Jang,

Nussinov

2024

J. Chem. Inf. Model.

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The Ras homologue family member A (RhoA) is a member of the Rho family, a subgroup of the Ras superfamily. RhoA interacts with the 115 kDa guanine nucleotide exchange factor (p115-RhoGEF), which assists in activation and binding with downstream effectors. Here, we use molecular dynamics (MD) simulations and essential dynamics analysis of the inactive RhoA− GDP and active RhoA−GTP, when bound to p115-RhoGEF to decipher the mechanism of RhoA activation at the structural level. We observe that inactive RhoA−GDP maintains its position near the catalytic site on the Dbl homology (DH) domain of p115-RhoGEF through the interaction of its Switch I region with the DH domain. We further show that the active RhoA−GTP is engaged in more interactions with the p115-RhoGEF membrane-bound Pleckstrin homology (PH) domain as compared to RhoA−GDP. We hypothesize that the role of the interactions between the active RhoA−GTP and the PH domain is to help release it from the DH domain upon activation. Our results support this premise, and our simulations uncover the beginning of this process and provide structural details. They also point to allosteric communication pathways that take part in RhoA activation to promote and strengthen the interaction between the active RhoA−GTP and the PH domain. Allosteric regulation also occurs among other members of the Rho superfamily. Collectively, we suggest that in the activation process, the role of the RhoA−GTP interaction with the PH domain is to release RhoA−GTP from the DH domain after activation, making it available to downstream effectors.

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Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2

Ging,

Frick,

Schlachetzki

et al. 2024

npj Parkinsons Dis.

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Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

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Pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) leads to the activation of RhoGTPases promoting the malignant phenotypes of thyroid cancer

Cited by 4 publications

References 20 publications

Direct and indirect regulation of β-glucocerebrosidase by the transcription factorsUSF2andONECUT2

Direct and indirect regulation of β-glucocerebrosidase by the transcription factorsUSF2andONECUT2

Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2

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