Oncogenic PIK3CA corrupts growth factor signaling specificity DOI Creative Commons
Ralitsa R. Madsen, Alix Le Marois, Oliwia N Mruk

и другие.

Molecular Systems Biology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 20, 2024

Abstract Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns the phosphoinositide 3-kinase (PI3K)/AKT pathway, and this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations PI3K-specific information transfer different factors. This features live-cell imaging PI3K/AKT reporters multiplexed CyTOF measurements RAS/ERK signaling markers over time. Using framework, we found that PIK3CA H1047R oncogene was not simple, constitutive activator as often presented. Dose-dependent expression human cervical cancer induced pluripotent stem cells corrupted fidelity factor-induced transfer, with preferential amplification epidermal receptor (EGFR) responses compared to insulin-like 1 (IGF1) insulin signaling. did only shift these higher mean but also enhanced heterogeneity. conclude corrupts factor-dependent manner suggest new opportunities tuning receptor-specific PI3K outputs therapeutic benefit.

Язык: Английский

Mitogen signaling strength and duration can control cell cycle decisions DOI Creative Commons
Ruth Nussinov, Wengang Zhang, Yonglan Liu

и другие.

Science Advances, Год журнала: 2024, Номер 10(27)

Опубликована: Июль 5, 2024

Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell critical for its decisions: proliferate or differentiate. Landmark publications established importance of mitogen not only in G 1 cycle phase but also through S 2 /M transition. Despite these early milestones, how signal strength, short strong weaker sustained, control fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) fluctuating mitogenic signals are converted into proliferation-differentiation decisions (ii) why extended weak is associated with differentiation, while bursts induce proliferation but, if too long, irreversible senescence. Our innovative broad outlook harnesses biology protein conformational ensembles, helping us define clarify decisions, thus fate.

Язык: Английский

Процитировано

14
Single-molecule lipid biosensors mitigate inhibition of endogenous effector proteins DOI Creative Commons

Victoria Holmes,

Morgan M.C. Ricci, Claire C. Weckerly

и другие.

The Journal of Cell Biology, Год журнала: 2025, Номер 224(3)

Опубликована: Янв. 11, 2025

Genetically encoded lipid biosensors uniquely provide real time, spatially resolved kinetic data for dynamics in living cells. Despite clear strengths, these tools have significant drawbacks; most notably, molecules bound to cannot engage with effectors, potentially inhibiting signaling. Here, we show that although PI 3-kinase (PI3K)-mediated activation of AKT is not significantly reduced a cell population transfected PH-AKT1 PIP3/PI(3,4)P2 biosensor, single cells expressing PH-AKT at visible levels activation. Tagging endogenous AKT1 neonGreen reveals its EGF-mediated translocation the plasma membrane. Co-transfection or other PIP3 eliminates this translocation, despite robust recruitment biosensors. Inhibition even observed PI(3,4)P2-selective biosensor. However, low levels, comparable those AKT, produced no such inhibition. Helpfully, single-molecule revealed improved dynamic range and fidelity compared overexpressed This approach represents noninvasive way probe spatiotemporal PI3K signaling

Язык: Английский

Процитировано

0
The Proteome of Exosomes at Birth Predicts Insulin Resistance, Adrenarche and Liver Fat in Childhood DOI Open Access
Marta Díaz, Tania Quesada‐López, Francesc Villarroya

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1721 - 1721

Опубликована: Фев. 18, 2025

It is unknown whether there are differentially expressed proteins (DEPs) in the circulating exosomes of appropriate- vs. small-for-gestational-age (AGA SGA) infants, and if so, such DEPs relate to measures endocrine-metabolic health body composition childhood. Proteomic analysis cord-blood-derived was performed by label-free quantitative mass spectrometry AGA (n = 20) SGA infants 91 were identified. Enrichment revealed that they related complement coagulation cascades, lipid metabolism, neural development, PI3K/Akt RAS/RAF/MAPK signaling pathways, phagocytosis focal adhesion. Protein-protein interaction (PPI) identified 39 involved pathways enriched KEGG Reactome. Those associated with adiposity insulin resistance liver fat at age 7 (all p < 0.01). Multivariate linear regression uncovered two (up-regulated SGA), namely PCYOX1 (related adipogenesis) HSP90AA1 metabolism metabolic-dysfunction-associated steatotic disease progression), independent predictors hepatic fraction (β 0.634; 0.002; R2 52% β 0.436; 0.009; 24%, respectively). These data suggest birth may predict resistance, adrenarche and/or ectopic children 7, when an early insulin-sensitizing intervention could be considered.

Язык: Английский

Процитировано

0
Identification of DIO2 as a Molecular Therapeutic Target for Depression in Chronic Rhinosinusitis: A Comprehensive Bioinformatics and Experimental Study DOI
Hao Lv, Peiqiang Liu, Yunfei Wang

и другие.

Biochemical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Март 16, 2025

Язык: Английский

Процитировано

0
The PIK3CA gene and its pivotal role in tumor tropism of triple-negative breast cancer DOI Creative Commons

Sumit Mallick,

Asim K. Duttaroy, Suman Dutta

и другие.

Translational Oncology, Год журнала: 2024, Номер 50, С. 102140 - 102140

Опубликована: Окт. 5, 2024

Язык: Английский

Процитировано

2
PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers DOI Creative Commons
Donghee Lee,

Emma Kozurek,

M. Abdullah

и другие.

Cancer Gene Therapy, Год журнала: 2024, Номер unknown

Опубликована: Дек. 21, 2024

Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies seemingly inflamed primarily due to their pathognomonic nature, which consists irregular endothelium and tortuous channels. PIK3CA mutations oncogenic disrupt the PI3K pathway. In this study, we aimed define molecular functional consequences in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring H1047R hotspot gene using CRISPR/Cas9. found PIK3CA-mutant cells established distinct signatures global expression chromatin accessibility, were associated with enrichment immune cytokine signaling, including IL-6, IL-8, MCP-1. processes disrupted by PI3K-α specific inhibitor, alpelisib. also observed distinctions linked metabolic reprogramming glycolytic activity mitochondrial respiration. Our multi-omics analysis revealed activating regulate machinery contributes phenotypic alterations resistance Furthermore, identified potential therapeutic vulnerabilities response inhibition mediated MAPK signaling. summary, demonstrate perpetuate activation reinforce promote drug cancers.

Язык: Английский

Процитировано

1
Akt Is Controlled by Bag5 through a Monoubiquitination to Polyubiquitination Switch DOI Open Access

Ismael Bracho‐Valdés,

Rodolfo Daniel Cervantes‐Villagrana, Yarely Mabell Beltrán‐Navarro

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(24), С. 17531 - 17531

Опубликована: Дек. 15, 2023

The serine-threonine kinase Akt plays a fundamental role in cell survival, metabolism, proliferation, and migration. To keep these essential processes under control, activity stability must be tightly regulated; otherwise, life-threatening conditions might prevail. Although it is well understood that phosphorylation regulates activity, much remains to known about how its maintained. Here, we characterize BAG5, chaperone regulator, as novel Akt-interactor substrate attenuates together with Hsp70. BAG5 switches monoubiquitination polyubiquitination of increases degradation caused by Hsp90 inhibition Hsp70 overexpression. interacts at the linker region joins first second BAG domains phosphorylates domain. Akt-BAG5 complex formed serum-starved dissociates response HGF, coincident phosphorylation. knockdown attenuated facilitated activation, whereas opposite effect was Altogether, our results indicate signaling are dynamically regulated depending on growth factor availability.

Язык: Английский

Процитировано

2
OncogenicPIK3CAcorrupts growth factor signaling specificity DOI Creative Commons
Ralitsa R. Madsen, Alix Le Marois, Oliwia N Mruk

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 23, 2023

Abstract Pathological activation of the PI3K/AKT pathway is among most frequent defects in human cancer and also cause rare overgrowth disorders. Yet, there currently no systematic understanding quantitative flow information within signaling how it perturbed by disease-causing mutations. Here, we develop scalable, single-cell approaches for analyses signal processing PI3K pathway, enabling precise calculations its transfer different growth factors. Using genetically-engineered cell models with allele dose-dependent expression PIK3CA H1047R , show that this oncogene not a simple, constitutive activator but context-dependent modulator extracellular transfer. reduces transmission downstream IGF1 while selectively enhancing EGF-induced transcriptional responses. This leads to gross reduction specificity, akin “blurred” perception. The associated increase heterogeneity promotes phenotypic diversity cervical line model induced pluripotent stem cells. Collectively, these findings accompanying methodological advances lay foundations mapping mechanisms PI3K/AKT-dependent control health disease. One-sentence summary Single-cell theoretic reveal oncogenic EGF response amplification as well increased heterogeneity.

Язык: Английский

Процитировано

2
Single molecule Lipid Biosensors Mitigate Inhibition of Endogenous Effector Proteins DOI Creative Commons

Victoria Holmes,

Morgan M.C. Ricci, Claire C. Weckerly

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 11, 2024

Genetically encoded lipid biosensors uniquely provide real time, spatially resolved kinetic data for dynamics in living cells. Despite clear strengths, these tools have significant drawbacks; most notably, molecules bound to cannot engage with effectors, potentially inhibiting signaling. Here, we show that although PI 3-kinase (PI3K)-mediated activation of Akt is not significantly reduced a cell population transfected PH-Akt1 PIP 3 /PI(3,4)P 2 biosensor, single cells expressing PH-Akt at visible levels activation. Tagging endogenous AKT1 neonGreen reveals its EGF-mediated translocation the plasma membrane. Co-transfection or other eliminates this translocation, despite robust recruitment biosensors. Inhibition even observed PI(3,4)P -selective biosensor. However, low levels, comparable those AKT, produced no such inhibition. Helpfully, single-molecule revealed improved dynamic range and fidelity compared over-expressed This approach represents non-invasive way probe spatiotemporal PI3K signaling eTOC summary Holmes colleagues AKT blocked by commonly used biosensors, but can be overcome molecule – which also improves sensitivity.

Язык: Английский

Процитировано

0
Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways DOI Open Access

Jinping Feng,

Xinan Zhang, Tianhai Tian

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 10204 - 10204

Опубликована: Сен. 23, 2024

The mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling cascade that plays a key role in various cellular processes. Understanding the regulatory mechanisms of this essential for developing effective interventions and targeted therapies related diseases. Recent advances single-cell proteomic technologies have provided unprecedented opportunities to investigate heterogeneity noise within complex, multi-signaling networks across diverse cells cell types. Mathematical modeling has become powerful interdisciplinary tool bridges mathematics experimental biology, providing valuable insights into these intricate In addition, statistical methods been developed infer topologies estimate unknown parameters dynamic models. This review presents comprehensive analysis how mathematical MAPK deepens our understanding its mechanisms, enhances prediction system behavior, informs research, with particular focus on recent inference using data.

Язык: Английский

Процитировано

0