bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2025–06–29
twelve papers selected by
Ralitsa Radostinova Madsen, MRC-PPU



  1. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jun 19. pii: S1388-1981(25)00060-5. [Epub ahead of print]1870(6): 159652
      Phosphoinositides are membrane-bound phospholipids that are derived from the reversible phosphorylation of phosphatidylinositol by the opposing actions of phosphoinositide kinases and phosphatases. Phosphoinositides are minor lipid constituents of cellular membranes; however, they assert a varied and profound influence on numerous biological processes both at the plasma membrane and on subcellular organelle membranes. Phosphoinositide phosphatases encompass multiple enzyme families that hydrolyze the phosphate group from the inositol ring of phosphoinositide species to modify signaling pathways that govern development and homeostasis. Genetic mutations that alter the function or expression of phosphoinositide phosphatases are causative of severe developmental syndromes or contribute to human diseases such as cancer, metabolic disorders and neuropathies. This review will focus on a select group of phosphoinositide phosphatase family members. Specifically, we will discuss the lipid and dual-specificity protein phosphatase PTEN, including the multiple regulatory mechanisms that define this enzyme as an established tumor suppressor. We will focus on recent discoveries that describe novel roles for phosphoinositide regulation on subcellular membranes by INPP5E and INPP5K, two members of the inositol polyphosphate 5-phosphatase family. Finally, the diverse biological and pathophysiological roles of the inositol polyphosphate 4-phosphatases, INPP4A and INPP4B, will be outlined. Collectively, these discussions will reveal the critical roles that phosphoinositide phosphatases play in both human development and for prevention of disease.
    Keywords:  INPP4B; INPP5E; INPP5K; PTEN; Phosphatase; Phosphoinositide
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159652
  2. J Cell Sci. 2025 Jun 15. pii: jcs263763. [Epub ahead of print]138(12):
      The p21-activated kinases (PAKs) are involved in a range of functions, including the regulation of the actin cytoskeleton. However, although many PAK substrates identified have been implicated in the regulation of the actin cytoskeleton, a coherent picture of the total effect of PAK activation on the state of the actin cytoskeleton is unclear. Here, we show that, in mouse embryonic fibroblasts, inhibition of class I PAK kinase activity by small-molecule inhibitors leads to the constitutive production of the phosphoinositide phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] on the ventral surface of the cell. The formation of patches of PI(3,4,5)P3 remodels the actin cytoskeleton and polarises the cell. From the overexpression of truncated and mutated PAK1 and PAK2 constructs, as well as an in vitro model of PAK activation, we propose that this is driven by a hyper recruitment of class I PAK and PAK-binding partners. This aberrant production of PI(3,4,5)P3 suggests that, by limiting its own recruitment, the kinase activity of class I PAKs acts to downregulate phosphoinositide 3-kinase (PI3K) activity, further highlighting class I PAKs as regulators of PI3K activity and therefore the excitability of the actin cytoskeleton.
    Keywords:  Actin; Actin waves; Excitability; PAK; PI3K
    DOI:  https://doi.org/10.1242/jcs.263763
  3. Cell. 2025 Jun 26. pii: S0092-8674(25)00675-0. [Epub ahead of print]188(13): 3370-3374
      Virtual cells are an emerging frontier at the intersection of artificial intelligence and biology. A key goal of these cell state models is predicting cellular responses to perturbations. The Virtual Cell Challenge is being established to catalyze progress toward this goal. This recurring and open benchmark competition from the Arc Institute will provide an evaluation framework, purpose-built datasets, and a venue for accelerating model development.
    DOI:  https://doi.org/10.1016/j.cell.2025.06.008
  4. iScience. 2025 Jun 20. 28(6): 112741
      PTEN acts as a tumor suppressor through its lipid and protein phosphatase activities. We previously reported that PTEN phosphatase inhibits metastasis independent of its lipid phosphatase. To determine PTEN phosphatase downstream substrates and their role precisely in metastatic suppression, we used proteomic approaches to identify PKCδ as PTEN protein phosphatase substrates. We show that the inactivation of PTEN protein phosphatase activity causes loss of the capability to dephosphorylate PKCδ at S643, T505, and Y311, but wild-type or PTEN lipid phosphatase deficient mutants can maintain. We then established knock-in and knock-out models to confirm that PTEN protein phosphatase is required to inhibit PKCδ phosphorylation and necessary to suppress tumor metastasis. Notably, we found that PKCδ could promote metastasis of melanoma cells with wild-type PTEN. Still, the knockdown of PKCδ abrogated the metastatic potential of PTEN phosphatase-deficient melanoma cells, linking PTEN metastasis suppressor function to PTEN protein phosphatase and its substrate PKCδ.
    Keywords:  Proteomics; cancer
    DOI:  https://doi.org/10.1016/j.isci.2025.112741
  5. Clin Cancer Res. 2025 Jun 27.
       PURPOSE: Activating mutations in AKT genes are rare but play an important role in the commonly dysregulated PI3K/AKT/mTOR signaling pathway. NCI-MATCH (EAY131) is a tumor agnostic platform trial that enrolled patients to targeted therapies based on matching tumor genomic alterations. Subprotocol Z1K evaluated ipatasertib, a pan-AKT inhibitor, in patients with AKT1E17K mutant metastatic tumors.
    METHODS: Patients received ipatasertib 400mg, orally once daily in a 28-day cycle until progression or unacceptable toxicity. Patients with known KRAS, NRAS, HRAS, or BRAF mutations were excluded. Prior PI3K and mTOR inhibitors were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and toxicity.
    RESULTS: Thirty-five patients were enrolled, and 29 patients were included in the prespecified primary efficacy analysis. Multiple histologies were enrolled, with breast (n = 18) and gynecologic (n = 7) being the most common. The majority had > 3 lines of therapy (19/29, 65.5%). The ORR was 24.1% (7/29, 90% CI, 11.9%-40.6%) with P < 0.001 against a null rate of 5%. All responses were partial responses. Median response duration was 10.1 months (90% CI, 3.7-10.8). The most common toxicities of any grade included diarrhea (n = 25), nausea (n = 13), and hyperglycemia (n = 9). Grade 3/4 toxicities observed were consistent with reported toxicities for AKT inhibition. Twelve grade 3 events occurred that were thought to be at least possibly related to treatment.
    CONCLUSIONS: The study met its primary endpoint with ipatasertib demonstrating clinically significant activity in heavily pretreated patients with various tumors harboring AKT1E17K mutations.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3431
  6. Cell Rep. 2025 Jun 24. pii: S2211-1247(25)00660-6. [Epub ahead of print]44(7): 115889
      Synapse formation is a fundamental process that shapes the connectivity and function of the nervous system, but the mechanisms regulating synaptogenesis are incompletely understood. Moreover, the interplay of these mechanisms at distinct synapse types remains to be defined. Using a scalable optical pooled screening platform, we investigated the process of synapse induction to uncover modulators of a prototypical synapse-organizing adhesion molecule, neuroligin-1. Analysis of over two million single-cell phenotypic profiles identified 102 candidate regulators of neuroligin-1 that are linked to cell adhesion, cytoskeletal dynamics, and signaling. Among these, we show that the phosphatase PTEN and the dystrophin-associated glycoprotein DAG1 promote neuroligin's roles in inducing presynaptic assembly, with DAG1 selectively regulating inhibitory synapses. This work establishes a scalable high-content screening approach for cell-cell interactions that enables systematic studies of the molecular interactions guiding synaptogenesis.
    Keywords:  CP: Neuroscience; CRISPR/Cas9; cell adhesion molecules; cell non-autonomous; cell-cell interactions; functional genomics; high-content screening; neuroligin; optical pooled screening; synapse; synaptogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115889
  7. Am J Physiol Heart Circ Physiol. 2025 Jun 27.
      Angiogenesis, a cornerstone of vascular development, tissue regeneration, and tumor progression, is critically orchestrated by the metabolic behavior of endothelial cells (ECs). Recent discoveries have redefined ECs not as metabolically uniform entities, but as spatially and functionally heterogeneous populations whose metabolic states govern their angiogenic potential. This review presents a comprehensive synthesis of metabolic zonation in ECs, spanning arterial, venous, and capillary domains, and highlights cell-type-specific programs during sprouting angiogenesis-including tip, stalk, and phalanx cells. We explore how distinct metabolic pathways-glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis-are differentially utilized across tissue contexts such as the brain, skeletal muscle, kidney, and tumor microenvironments. We discuss technological breakthroughs in spatial metabolomics, temporal (circadian) regulation of endothelial metabolism, and emerging clinical strategies to target EC metabolic vulnerabilities in cancer and ischemic diseases. Furthermore, we advocate for spatiotemporal modeling of EC metabolism using computational and machine learning frameworks to predict angiogenic behavior and accelerate therapeutic discovery. This integrative perspective underscores the need for precision-targeted angiogenic interventions and establishes metabolic zonation as a foundational principle in vascular biology.
    Keywords:  angiogenesis; endothelial cell; energy; glycolysis; metabolism
    DOI:  https://doi.org/10.1152/ajpheart.00352.2025
  8. Cell. 2025 Jun 19. pii: S0092-8674(25)00624-5. [Epub ahead of print]
      Next-generation sequencing is pivotal for diagnosing inborn errors of immunity (IEI) but predominantly yields variants of uncertain significance (VUS), creating clinical ambiguity. Activated PI3Kδ syndrome (APDS) is caused by gain-of-function (GOF) variants in PIK3CD or PIK3R1, which encode the PI3Kδ heterodimer. We performed massively parallel base editing of PIK3CD/PIK3R1 in human T cells and mapped thousands of variants to a clinically important readout (phospho-AKT/S6), nominating >100 VUS and unannotated variants for functional classification and validating 27 hits. Leniolisib, an FDA-approved PI3Kδ inhibitor, rescued aberrant signaling and dysfunction in GOF-harboring T cells and revealed partially drug-resistant PIK3R1 hotspots that responded to novel combination therapies of leniolisib with mTORC1/2 inhibition. We confirmed these findings in T cells from APDS patients spanning the functional spectrum discovered in the screen. Integrating our screens with population-level genomic studies revealed that APDS may be more prevalent than previously estimated. This work exemplifies a broadly applicable framework for removing ambiguity from sequencing in IEI.
    Keywords:  APDS; CRISPR base editing; VUS; activated PI3K delta syndrome; clinical NGS; genome engineering; inborn errors of immunity; precision medicine; primary T cells; variant classification
    DOI:  https://doi.org/10.1016/j.cell.2025.05.037
  9. Sci Transl Med. 2025 Jun 25. 17(804): eadq7825
      Crescentic glomerulonephritis (cGN) is a severe kidney pathology characterized by the aberrant proliferation of epithelial cells, leading to crescent formation within the Bowman's space. The molecular pathways involved in crescent formation remain poorly understood despite its clinical relevance. Given the mechanical stress experienced by podocytes, likely exacerbated in cGN, we hypothesized that activation of the mechanosensor yes-associated protein 1 (YAP), an effector of the Hippo pathway, may contribute to the development of cGN. Here, we demonstrate activation of YAP and its target genes in the nephrotoxic nephritis model, a murine model of cGN. Mechanistically, podocyte-specific hyperactivation of YAP (YAP5SA) in transgenic mice led to cell-autonomous hypertrophy of podocytes and non-cell-autonomous activation and proliferation of parietal epithelial cells (PECs), culminating in crescents. Transcriptomic profiling in a human podocyte cell line expressing the same YAP5SA isoform revealed the reactivation of developmental programs within differentiated podocytes and identified the phosphoinositide 3-kinase-protein kinase B-mechanistic target of rapamycin (PI3K-Akt-mTOR) signaling pathway as a candidate involved in YAP-induced podocyte hypertrophy. Furthermore, this analysis identified connective tissue growth factor (CTGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) as potential mediators in the cross-talk between YAP-activated podocytes and PECs, driving PEC hyperplasia. Collectively, these findings highlight the pivotal role of YAP in the pathogenesis of cGN and indicate that targeting YAP signaling could be a promising therapeutic strategy for this severe kidney disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adq7825
  10. Blood. 2025 Jun 25. pii: blood.2025028454. [Epub ahead of print]
      Liver sinusoidal endothelial cells (LSECs) are essential for maintaining liver function by actively sensing nutrients and producing angiocrine factors. LSECs also regulate systemic iron metabolism by secreting bone morphogenetic proteins (BMPs), key modulators of systemic iron homeostasis. However, the mechanism by which LSECs sense iron to regulate iron metabolism remains unclear. Here, we identify that the endothelial transcriptional factor Foxo1 and its upstream protein kinase, mTORC2, as critical iron-sensors. In response to iron, Foxo1 undergoes acute and dynamic nuclear translocation to activate the transcription of Bmp2 and Bmp6, thereby stimulating the synthesis of iron-regulatory hormone hepcidin in adjacent hepatocytes. Foxo1 directly binds evolutionally conserved Foxo binding sites within the Bmp2 and Bmp6 promoters to mediate this response. Mechanistically, iron triggers the lysosomal degradation of the mTORC2-specific component Rictor, enhancing Foxo1 activation. Endothelial-specific Foxo1 deletion reduces the expressions of hepatic Bmp2/6 and hepcidin, leading to systemic iron overload, whereas endothelial Rictor deletion increases the expressions of hepatic Bmp2/6 and hepcidin, producing an iron-deficient phenotype. Moreover, endothelial-targeted lipid nanoparticles expressing endothelial-specific and constitutively active Foxo1 alleviate iron overload in a murine model of hereditary hemochromatosis. Collectively, our study establishes the endothelial mTORC2-Foxo1 axis as an iron-responsive regulator of Bmp2 and Bmp6 expressions, and identifies it as a promising target for iron-related disorders.
    DOI:  https://doi.org/10.1182/blood.2025028454
  11. EMBO J. 2025 Jun 23.
      Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.
    Keywords:  Cell Cycle; Cell Cycle Checkpoints; DNA Damage; Mitosis
    DOI:  https://doi.org/10.1038/s44318-025-00495-0
  12. bioRxiv. 2025 May 28. pii: 2025.05.23.655625. [Epub ahead of print]
      Mutations in PIK3R1 , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1 c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.
    DOI:  https://doi.org/10.1101/2025.05.23.655625