bims-raghud 2025-07-13 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–07–13
seven papers selected by
Irene Sambri, TIGEM

Evolution of growth factor signaling to the TSC complex to regulate mTORC1.
The polarity protein Par3 enhances renal cell carcinoma metastasis via YAP/TAZ activation.
Modulation of infiltrating CD206-positive macrophages restricts progression of pulmonary lymphangioleiomyomatosis (LAM).
Genetic analysis of a novel TSC1 splice mutation causing tuberous sclerosis without neurological phenotypes.
Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.
Vascular transcriptional and metabolic changes precede progressive intra-renal microvascular rarefaction in autosomal dominant polycystic kidney disease.
Regulation of partial endothelial-to-mesenchymal transition by circATXN1 in ischemic diseases.

Sci Signal. 2025 Jul 08. 18(894): eadw4165

Evolution of growth factor signaling to the TSC complex to regulate mTORC1.

Kun Wang, Sophie E Lockwood, Brendan D Manning.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1 activation and its promotion of cell growth. Cryo-electron microscopy studies of the TSC protein complex have revealed that this phosphoregulation of TSC2 occurs almost exclusively on residues in loops that are outside of the evolutionarily conserved core structural elements and that did not resolve in these structures. These phosphorylation-rich unstructured loops evolved with metazoans, suggesting that the regulation of mTORC1 by diverse growth factors likely evolved with the emergence of complex body plans and diverse cell types to coordinate cell growth and metabolism within and across distinct tissues. Unlike the core structure of TSC2, these loops lack disease-associated missense mutations. These features suggest that the regulatory loops on TSC2 are more amenable to evolutionary changes that enable diverse signals to converge on the TSC protein complex to regulate mTORC1.

DOI: https://doi.org/10.1126/scisignal.adw4165
Cancer Biol Med. 2025 Jul 08. pii: j.issn.2095-3941.2024.0297. [Epub ahead of print]

The polarity protein Par3 enhances renal cell carcinoma metastasis via YAP/TAZ activation.

Soo Lee, Jonathan Balcazar, Karla Davis, Rey-Chen Pong, Jer-Tsong Hsieh, Payal Kapur, Xiaosong Meng.

   OBJECTIVE: Partitioning defective protein 3 (Par3) has recently been found to have important roles in cancer progression. Interestingly, Par3's functions vary among cancers: both Par3 elevation (in the prostate or liver) and loss (in the breast or lung) have been implicated in cancer metastasis. Although Par3 overexpression has been correlated with diminished survival in renal cell carcinoma (RCC), data indicating the role of Par3 in RCC metastasis are lacking. Given reports of interactions between Par3 and oncoproteins such as Yes-associated protein (YAP)/WW domain-containing transcription regulator 1 (TAZ), we investigated whether Par3-mediated RCC metastasis might be due to activation of the Hippo pathway components YAP and TAZ.
METHODS: Par3 levels were analyzed in RCC cell lines and human RCC patient tissues by western blotting and immunohistochemical (IHC) staining, as appropriate. Co-immunoprecipitation (co-IP) and immunofluorescence studies were conducted to examine the interaction between Par3 and YAP. Quantitative PCR and luciferase assays were used to investigate the effects of Par3 on YAP target gene expression and co-transcriptional regulation. PDZ domain deletion mutants of Par3 were generated to elucidate the structural basis of the interaction between Par3 and YAP.
RESULTS: Higher Par3 levels were found in distant-organ-RCC-metastasis-derived ACHN sublines than wild type ACHN cell lines. Par3 levels were also higher in the patient tissue obtained from metastatic sites than in normal kidney and primary RCC tumor tissues. Co-IP and IHC experiments demonstrated that Par3 directly interacted and co-localized with YAP/TAZ proteins. Moreover, Par3 upregulated the transcription of YAP/TAZ downstream target genes and increased the luciferase activity of YAP/TAZ responsive elements. PDZ domain 3 in the PARD3 gene was demonstrated to be particularly important in the interactions between Par3 and YAP. Furthermore, Par3 was found to upregulate intracellular levels of YAP/TAZ molecules and promote nuclear translocation of YAP.
CONCLUSIONS: Together, these results indicate the role of Par3 in RCC metastasis, via driving metastatic RCC progression by promoting the YAP/TAZ pathway.

Keywords:  Par3; Renal cell carcinoma (RCC); YAP; metastasis

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0297
Eur Respir J. 2025 Jul 10. pii: 2500084. [Epub ahead of print]

Modulation of infiltrating CD206-positive macrophages restricts progression of pulmonary lymphangioleiomyomatosis (LAM).

Heng-Jia Liu, Remi Diesler, Joelle Chami, Boxiang Wu, Heng Du, Yue Jin, Melissa Daou, Nicola Alesi, Damir Khabibullin, Caroline Leroux, Vincent Cottin, Lloyd G Cantley, Udo Rudloff, Elizabeth P Henske.

RATIONALE: Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC)1 or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown.
METHODS: To identify the different immune cells populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterize the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumors treated with RP-182, a synthetic peptide which reprograms macrophages towards an anti-tumor M1-like phenotype.
RESULTS: Single-cell RNA-seq analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells which are in close proximity to macrophages highly express macrophage homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2 markers expressed macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumors in vivo.
CONCLUSION: LAM cells recruit and polarize macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.

DOI: https://doi.org/10.1183/13993003.00084-2025
Sci Rep. 2025 Jul 09. 15(1): 24780

Genetic analysis of a novel TSC1 splice mutation causing tuberous sclerosis without neurological phenotypes.

Xiu-Juan Yao, Ying Lin, Jing Zou, Zun-Lin Cai, Zi-Yan Xu, Xiao-Qin Li, Qian Chen, Hong-Ping Yu, Jian-Hui Zhang, Dan-Dan Ruan, Mei-Zhu Gao, Li Zhang, Jie-Wei Luo, Bao-Song Xie.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of benign tumors and lesions in multiple organ systems. The syndrome arises from heterozygous mutations in either TSC1 or TSC2. In this study, we identified a family with a TSC1 c.363 + 668G > C mutation exhibiting diverse clinical phenotypes. The proband and affected family members exhibited multifocal nodular pneumocyte hyperplasia (MMPH), renal hamartomas, bone marrow hyperplasia, and pulmonary lymphangioleiomyomatosis (LAM), with genetic co-segregation analysis confirming the association between the mutation and the clinical phenotype. Genetic co-segregation analysis demonstrated that the TSC1 c.363 + 668G > C mutation was consistently associated with the observed clinical features in this family. Using first-generation Sanger sequencing, we identified a heterozygous splicing variation located in intron 5 of TSC1 (NM_000368.5). In vitro cell and family Minigene results show that TSC1 c.363 + 668G > C mutation can lead to abnormal retention of 92 bp intron sequence in different positions, which may be related to the alternative splicing phenomenon that the same gene produces different splicing variants in different tissues or development stages. The 3D protein structure analysis using Chimera revealed that the mutation site was located at the 363rd base, within the intron between the 121st and 122nd amino acids. This mutation resulted in the insertion of a 92-base sequence, causing a frameshift that led to premature termination of the TSC1 protein after the translation of 26 amino acids. Additionally, the 121st amino acid was altered from lysine to asparagine, significantly shortening the mutated TSC1 protein. These findings provide critical experimental evidence supporting the potential pathogenic mechanism of the TSC1 c.363 + 668G > C mutation. Future research should focus on validating this splicing abnormality in patient-derived cells or tissues and investigating its impact on protein expression and functional activity to better understand its role in disease progression.Clinical trial number: K2024-09-144.

DOI: https://doi.org/10.1038/s41598-025-07906-6
EMBO Rep. 2025 Jul 07.

Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.

Hao Li, Yohei Kanamori, Akihiro Nita, Ayato Maeda, Tianli Zhang, Kenta Kikuchi, Hiroyuki Yamada, Touya Toyomoto, Mohamed Fathi Saleh, Mayumi Niimura, Hironori Hinokuma, Mayuko Shimoda, Koei Ikeda, Makoto Suzuki, Yoshihiro Komohara, Daisuke Kurotaki, Tomohiro Sawa, Toshiro Moroishi.

  Recent advances in single-cell technologies have uncovered significant cellular diversity in tumors, influencing cancer progression and treatment outcomes. The Hippo pathway controls cell proliferation through its downstream effectors: yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Our analysis of human lung adenocarcinoma and murine models revealed that cancer cells display heterogeneous YAP/TAZ activation levels within tumors. Murine lung cancer cells with high YAP/TAZ activity grow rapidly but are sensitive to ferroptosis, a cell death induced by lipid peroxidation. In contrast, cells with low YAP/TAZ activity grow slowly but resist ferroptosis. Moreover, they protect neighbouring cells from ferroptosis, creating a protective microenvironment that enhances the tumor's resistance to ferroptosis. Mechanistically, inhibiting YAP/TAZ upregulates GTP cyclohydrolase 1 (GCH1), an enzyme critical for the biosynthesis of tetrahydrobiopterin (BH4), which functions as a secretory antioxidant to prevent lipid peroxidation. Pharmacological inhibition of GCH1 sensitizes lung cancer cells to ferroptosis inducers, suggesting a potential therapeutic approach. Our data highlights the non-cell-autonomous roles of the Hippo pathway in creating a ferroptosis-resistant tumor microenvironment.

Keywords:  Biopterin; Cell Communication; Ferroptosis; Hippo Pathway; Lung Cancer

DOI:  https://doi.org/10.1038/s44319-025-00515-4
bioRxiv. 2025 Jul 04. pii: 2025.06.30.662386. [Epub ahead of print]

Vascular transcriptional and metabolic changes precede progressive intra-renal microvascular rarefaction in autosomal dominant polycystic kidney disease.

Gizem Yilmaz, Santu K Singha, Bansi Savaliya, Ahmed Abdelfattah, Walaa Elsekaily, Xiaohong Xu, Youwen Zhang, Christian Hanna, Marie C Hogan, Alejandro R Chade, Alfonso Eirin, Maria V Irazabal.

Background: The mechanisms contributing to progressive kidney damage in autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Renal microvascular (MV) rarefaction plays an important role in kidney disease, but its natural history, underlying mechanisms, and contributions to renal disease progression in ADPKD remain unknown. We hypothesized that intrarenal MV rarefaction is present early on and is preceded by vascular transcriptional and metabolic changes.
Methods: Pkd1RC/RC and WT mice (n=16 each) were studied at 1, 6, and 12 months. Total kidney volume (TKV) was measured in vivo (MRI), whereas renal MV architecture (3D-micro-CT), capillary density, perivascular fibrosis, and histomorphometric parameters were assessed ex vivo . In randomly selected Pkd1 RC/RC and WT kidneys (n=5, each/timepoint), mRNA-sequencing was performed to identify differentially expressed vasculature-related genes (DEGs). Next, in young individuals with ADPKD and matched controls (n=10 each), plasma cellular energy metabolites were determined (LC-MS/MS), validated in an extended cohort (n=32 and n=16, respectively), and correlated with markers of disease severity and progression. Gene-metabolite interaction networks were generated to integrate DEGs in Pkd1 RC/RC at 1 month with metabolites dysregulated in individuals with ADPKD.
Results: Renal MV density was preserved at 1 month but progressively decreased at 6 and 12 months, associated with capillary loss and perivascular fibrosis. A total of 110, 48, and 201 DEGs were identified at 1, 6, and 12 months, respectively. Plasma gamma-aminobutyric acid (GABA) and homocysteine (Hcy) levels were higher in individuals with ADPKD versus controls, interacted with DEGs implicated in inflammatory and innate immune response and Hcy metabolism, and correlated with TKV and renal blood flow.
Conclusions: Our data demonstrates that intrarenal MV abnormalities present early in ADPKD and are preceded by vascular transcriptional and metabolic changes. The renal microcirculation may constitute an important therapeutic target in ADPKD, and its underlying biomarkers may serve to monitor its progression.
TRANSLATIONAL STATEMENT: We provide the first longitudinal and most comprehensive analysis of the intrarenal microvascular network in a slowly progressive orthologous model of ADPKD and integrate the findings with studies in a young cohort of ADPKD individuals. Our integrated preclinical and clinical data identify vasculature-related pathways that could be targeted for therapeutic interventions and contribute promising, noninvasive biomarkers in patients with ADPKD. Furthermore, because alterations of the intrarenal microcirculation may affect drug delivery, a better understanding of its longitudinal changes may aid in treatment management.

DOI: https://doi.org/10.1101/2025.06.30.662386
Nat Commun. 2025 Jul 10. 16(1): 6357

Regulation of partial endothelial-to-mesenchymal transition by circATXN1 in ischemic diseases.

Yue Li, Zhe Zheng, Yanze Li, Siyuan Fan, Lingyao Kong, Wanrong Fu, Zhonggen Li, Jianchao Zhang, Shuang Li, Zongtao Liu, Chao Liu, Jinhua Cao, Zhenxuan Hao, Lili Xiao, Youyou Du, Xiaofang Wang, Lu Gao.

Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poorly defined. To address this, we performed circular RNA profiling of endothelial cells under ischemic-like conditions and identified a marked upregulation of a circular RNA, named circATXN1. Functional studies revealed that circATXN1 knockdown modulates endothelial phenotype and vascular response after ischemia. Functional studies have shown that knockdown of circATXN1 can regulate the endothelial cell phenotype and vascular response after ischemia. Mechanistically, circATXN1 knockdown enhances the demethylase protein ALKBH5 to reduce the RNA methylation level of the key transcription factor SLUG, thereby stabilizing SLUG. In animal models, suppression of circATXN1 enhances angiogenesis and improves recovery following ischemic injury. Here, we show that circATXN1 regulates partial endothelial-to-mesenchymal transition (EndMT) and angiogenesis by controlling SLUG mRNA methylation dynamics, highlighting its potential as a therapeutic target in ischemic disease.

DOI: https://doi.org/10.1038/s41467-025-61596-2