bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–07–20
eight papers selected by
Irene Sambri, TIGEM
  1. Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
  2. Exploring Hippo YAP/TAZ Signaling: A Novel Avenue for Cardiovascular Disorders.
  3. Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.
  4. New insights into tuberous sclerosis complex: from structure to pathogenesis.
  5. Cardiorenal Syndrome in Adults with Congenital Heart Disease.
  6. Autophagy paradox: Genetic and epigenetic control of autophagy in cancer progression.
  7. mtKO: A dedicated guide RNA library for mitochondria research.
  8. Hippo/YAP signaling's multifaceted crosstalk in cancer.
  1. bioRxiv. 2025 May 07. pii: 2025.05.07.652626. [Epub ahead of print]
    Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
    Jong Shin, Yann Cormerais, Khaled Tighanimine, Pratima Niroula, Madi Y Cisse, Samuel C Lapp, Krystle C Kalafut, Sandra Schrötter, Brendan D Manning.
      The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), as a sensor of growth signals that subsequently controls cell growth, has been predominantly studied in actively proliferating cells. Primary cilia are sensory organelles present on most quiescent cells, where they play essential roles in receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences the growth of primary cilia. Here, we show that mTORC1 promotes primary cilia elongation, without effects on ciliogenesis or cell growth, by suppressing autophagy. Inhibition of mTORC1 signaling through pharmacological, nutritional, or genetic interventions gave rise to shortened primary cilia, while activation of the pathway resulted in elongation. Furthermore, pharmacological or genetic inhibition of autophagy, a key downstream process blocked by mTORC1, also elongated primary cilia and rendered them resistant to mTORC1 inhibition. Notably, these mTORC1-mediated effects on primary cilia extend to mouse neurons ex vivo and in vivo. These findings highlight a previously unrecognized role for mTORC1 signaling in the control of primary cilia length that may contribute to diseases where ciliary function is altered, referred to as ciliopathies.
    DOI:  https://doi.org/10.1101/2025.05.07.652626
  2. Cell Biol Int. 2025 Jul 14.
    Exploring Hippo YAP/TAZ Signaling: A Novel Avenue for Cardiovascular Disorders.
    Arwa Mithaiwala, Angel Godad.
      Significant attention has been paid to the Hippo signaling pathway and its effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in cellular proliferation, survival, tissue homeostasis during development as well as cancer. While initially investigated in the context of oncogenesis, recent studies have just indicated its importance to cardiovascular diseases (CVD) like cardiac myocardial infarction (MI), cardiac hypertrophy, and heart failure (HF). This review focuses on therapeutic targets, regulatory mechanisms and signaling crosstalk between Hippo YAP/TAZ pathway with other traditional pathways like PI3K/AKT, TGF-β, WNT/β-catenin in CVD. Thus, although targeted YAP/TAZ activation in the myocardium may enhance regeneration/differentiation, its dysregulation promotes maladaptive cardiac remodeling characterized by hypertrophy and fibrosis. A better appreciation of the nuanced control on YAP/TAZ in different cardiovascular indications may point to an opportunity for precision therapeutics. In this review, we have discussed strategies to target specific components of the Hippo pathway as potential therapeutic approaches with implications for fibrosis reduction by LATS1/2 inhibition or cardiomyocyte survival promotion via MST1/2 suppression. The role of noncoding RNAs in YAP/TAZ activity modulation is further illustrated and provides us with possible therapeutic avenues that can be explored for noninvasive treatments.
    Keywords:  Hippo signaling pathway; TAZ; YAP; cardiovascular disorders; noncoding RNA; regenerative medicine; therapeutic targets
    DOI:  https://doi.org/10.1002/cbin.70052
  3. Cell Mol Biol Lett. 2025 Jul 17. 30(1): 83
    Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.
    Zhenxiong Zhang, Peiheng He, Li Yang, Jun Gong, Renyi Qin, Min Wang.
      Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.
    Keywords:  Hippo; Pathogenesis; Posttranslational modifications; TAZ; YAP
    DOI:  https://doi.org/10.1186/s11658-025-00760-4
  4. Front Cell Dev Biol. 2025 ;13 1595867
    New insights into tuberous sclerosis complex: from structure to pathogenesis.
    Chao-Sheng Chen, Christopher H S Aylett.
      Tuberous sclerosis complex is a genetic disorder characterised by the formation of benign tumours in multiple organs, primarily due to pathogenic variants in the TSC1 and TSC2 tumour suppressor genes. These genes encode hamartin and tuberin, respectively, which together with TBC1D7 form a crucial protein complex regulating cell growth and proliferation through mTOR signalling and other pathways. This review provides an overview of recent progress in understanding the molecular structure and function of this key protein complex, its role in cellular processes, pathogenesis, and current and future therapeutic strategies.
    Keywords:  GAP; RHEB; TBC1D7; TSC; hamartin; mTORC1; rapamycin; tuberin
    DOI:  https://doi.org/10.3389/fcell.2025.1595867
  5. J Clin Med. 2025 Jun 20. pii: 4392. [Epub ahead of print]14(13):
    Cardiorenal Syndrome in Adults with Congenital Heart Disease.
    Shailendra Upadhyay, Anudeep K Dodeja, Olga Toro-Salazar, Whitney Fairchild, Frank Han.
      As the population of adults with congenital heart disease (ACHD) continues to grow, a significant and often underrecognized complication is the development of cardiorenal syndrome (CRS)-a complex, bidirectional interaction between cardiac and renal dysfunction. While CRS has been extensively studied in acquired heart failure, its manifestations and implications in ACHD remain insufficiently understood. Emerging data suggest that renal dysfunction is highly prevalent in ACHD, with significant associations to adverse outcomes regardless of cardiac lesion type or functional status. This review explores CRS within three key physiologic categories in ACHD: patients with a systemic right ventricle, those with a subpulmonary right ventricle, and those with Fontan circulation. Each subgroup presents unique hemodynamic challenges that affect renal perfusion, filtration pressure, and systemic congestion, contributing to both acute and chronic renal impairment. The utility of renal biomarkers such as albuminuria, cystatin C, and estimated glomerular filtration rate (eGFR) is emphasized, alongside the importance of early detection and multidisciplinary management. Heart failure therapy tailored to congenital anatomy, neurohormonal modulation, and careful volume control remain the cornerstones of treatment, while transplantation strategies must consider the potential for irreversible end-organ damage. Given the profound implications of CRS on quality of life and survival, a comprehensive understanding of its pathophysiology and management in ACHD is critical to optimizing long-term outcomes in this increasingly complex patient population.
    Keywords:  Fontan circulation; adult congenital heart disease; cardio renal syndrome; heart failure; systemic right ventricle
    DOI:  https://doi.org/10.3390/jcm14134392
  6. Cancer Lett. 2025 Jul 09. pii: S0304-3835(25)00477-X. [Epub ahead of print]630 217909
    Autophagy paradox: Genetic and epigenetic control of autophagy in cancer progression.
    Chandra Sekhar Bhol, Prakash Kumar Senapati, Rakesh Kumar Kar, Grace Chew, Kewal Kumar Mahapatra, E Hui Clarissa Lee, Alan Prem Kumar, Sujit Kumar Bhutia, Gautam Sethi.
      Autophagy is a highly regulated, evolutionarily conserved process of self-digestion controlled by autophagy-related (ATG) genes. It involves the lysosomal degradation of cargoes, including cytoplasmic organelles, misfolded proteins, and toxic aggregates, to enrich cellular nutrient pools and reduce oxidative stress. In normal cells, basal autophagy occurs to maintain cellular homeostasis, which changes during tumor initiation, progression, and malignant transformation. The alteration in autophagy in cancer remains unclear and under-explored. Research indicates that genetic regulations, such as gene mutations, gene polymorphisms, or epigenetic modifications, including DNA methylation, histone modification, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), regulate ATGs, orchestrating the fluctuating nature of autophagy in cancer. Many studies describe the paradoxical role of autophagy in cancer, portraying it as a double-edged sword depending on the context, oscillating between promoting cell survival and inducing cell death-the dual roles in preventing tumor initiation and supporting tumor progression place autophagy at the centre of controversy. Recent findings suggest that autophagy is regulated at the intrinsic cellular level and within the tumor microenvironment. Thus, identifying the molecules, mediators, and mechanisms associated with the regulation of autophagy during tumor development, maintenance, therapy resistance, and dormancy could open new research avenues to enhance the efficacy of cancer therapeutics. Furthermore, this review encompasses preclinical studies and clinical trials, highlighting the effectiveness of modulating autophagy in cancer therapy.
    Keywords:  Autophagy; Cancer; DNA methylation; Gene polymorphism; Genetic mutation; Histone modification; lncRNA; miRNA
    DOI:  https://doi.org/10.1016/j.canlet.2025.217909
  7. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2502285122
    mtKO: A dedicated guide RNA library for mitochondria research.
    Karambir Kaur, Javeria Zaheer, Fengchao Lang, Diego Luis Ribeiro, Meili Zhang, Hua Song, Wei Zhang, Raj Chari, Hussam Alkaissi, Chunzhang Yang.
      Mitochondria are multifunctional organelles central to both physiological and pathological processes. In malignant cancer cells, mitochondrial reprogramming establishes the metabolic foundation to meet cellular demands, which is particularly important in tumor cells with existing metabolic perturbations. To identify key mitochondrial pathways supporting cancer development, we developed mitochondria Knockout (mtKO), a robust and unbiased CRISPR screening platform to pinpoint critical mitochondria-associated pathways. The mtKO screen revealed that the mitochondrial antioxidant enzyme SOD2 is essential for cells harboring IDH1 mutations. Mechanistically, SOD2 activity determines the disease manifestation of IDH1-mutated cancers, through maintaining redox homeostasis and mitochondrial fitness. This study introduces a powerful functional genomic tool to identify mitochondrial-centered pathways and reveals the selective mitochondrial vulnerability in Krebs cycle-deficient cancers for future therapeutic intervention.
    Keywords:  CRISPR screen; IDH1; SOD2; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2502285122
  8. Front Cell Dev Biol. 2025 ;13 1595362
    Hippo/YAP signaling's multifaceted crosstalk in cancer.
    Jie Zhang, Haipeng Wu, Xinxin Ren, Zhuoshi Chen, Siyu Ye, Shuchang Chen, Jie Fang, Qirou Wu, Tiejun Zhao.
      The Hippo/yes-associated protein (YAP) signaling is an evolutionarily conserved regulator in organ size control, which plays pivotal roles in cell proliferation, differentiation, apoptosis, and tissue regeneration. In cancer, dysregulation of Hippo/YAP signaling is typically recognized as one of the crucial drivers in tumorigenesis. However, beyond its canonical transcriptional targets, Hippo/YAP signaling engages in extensive crosstalk with multiple pathways to form an intricate regulatory network, thereby giving rise to its content-dependent influence on tumor initiation, progression and metastasis. This review focuses on the molecular mechanisms underlying the interplay between Hippo/YAP and pivotal signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), wingless-type (Wnt)/β-catenin signaling pathway, transforming growth factor-beta (TGF-β), Hedgehog, Notch and other signaling pathways, as well as their implications in cancer biology. Ultimately, exploiting these mechanisms may represent promising therapeutic strategies for cancer.
    Keywords:  Hippo/YAP signaling; cancer; crosstalk; signaling pathway; therapeutic target
    DOI:  https://doi.org/10.3389/fcell.2025.1595362
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒20 at 4:01.