ERK signaling for cell migration and invasion

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Окт. 3, 2022

The RAS - Extracellular signal-regulated kinase (RAS-ERK) pathway plays a conserved role in promoting cell migration and invasion. Growth factors, adhesion, oncogenes activate ERK. While historically studied with respect to its control of proliferation differentiation, the signaling pattern effectors specific for are now coming light. New advances probes have revealed how steady-state ERK activity fluctuates within individual cells propagates neighboring cells. We review new findings on different modes stimulation an increased baseline level promotes single collective discuss drives actin polymerization adhesion turnover edge protrusion contraction stimulates movement waves epithelial sheets. With steady development biosensors monitoring spatial temporal activity, determining individually interpret multiple vivo signals is reach.

Язык: Английский

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Specificity models in MAPK cascade signaling

FEBS Open Bio, Год журнала: 2023, Номер 13(7), С. 1177 - 1192

Опубликована: Май 9, 2023

The precise execution of various cellular functions relies on the maintenance signaling specificity from input detection to outputs. However, diverse pathways share similar or identical intermediate components. A well-conserved intermediate, Mitogen-Activated Protein Kinase (MAPK) cascade, participates in a myriad pathways, regulating signal transduction output. This typifies "hourglass conundrum", where multitude inputs and outputs all operate through limited number common intermediates. Therefore, understanding how MAPK cascades regulate variety with is fundamental question biology. review highlights four major insulating mechanisms that improve specificity: selective activation, compartmentalization, combinatorial signaling, cross-pathway inhibition. We focus plant cascade components compare those animals yeast. hope this conceptual overview will aid future studies better understand specificity.

Язык: Английский

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CD44 and Ezrin restrict EGF receptor mobility to generate a novel spatial arrangement of cytoskeletal signaling modules driving bleb–based migration

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Cells under high confinement form highly polarized hydrostatic pressure-driven, stable leader blebs that enable efficient migration in low adhesion, environments. Here we investigated the basis of bleb morphology metastatic melanoma cells migrating non-adhesive confinement. Using high-resolution time-lapse imaging and specific molecular perturbations, found EGF signaling via PI3K stabilizes maintains a bleb. Protein activity biosensors revealed unique EGFR/PI3K gradient decreasing from rear-to-front, promoting PIP3 Rac1-GTP accumulation at rear, with its antagonists PIP2 RhoA-GTP concentrated tip, opposite to front-to-rear organization these modules integrin-mediated mesenchymal migration. Optogenetic experiments showed disrupting this caused retraction, underscoring role stability. Mathematical modeling identified mechanism where, as initiates, CD44 ERM proteins restrict EGFR mobility membrane-apposed cortical actin meshwork establishing rear-to-front EGFR-PI3K-Rac gradient. Thus, our study reveals biophysical underpinnings cell polarity bleb-based confinement, underscores how alternative spatial arrangements can mediate different modes according local microenvironment.

Язык: Английский

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ERK activation waves coordinate mechanical cell competition leading to collective elimination via extrusion of bacterially infected cells

Cell Reports, Год журнала: 2025, Номер 44(1), С. 115193 - 115193

Опубликована: Янв. 1, 2025

Epithelial cells respond to infection with the intracellular bacterial pathogen Listeria monocytogenes by altering their mechanics promote collective infected cell extrusion (CICE) and limit spread across monolayers. However, underlying biochemical pathways remain elusive. Here, using in vitro (epithelial monolayers) vivo (zebrafish larvae) models of L. or Shigella flexneri, we explored role extracellular-signal-regulated kinase (ERK) activity waves coordinating mechanical battle between surrounder uninfected that leads CICE. We discovered when ERK are suppressed, fail exhibit alterations shape kinematics associated CICE behave more like quiescent In particular, surrounding foci unable polarize, reinforce monolayer stresses, Our findings reveal crosstalk is key elimination large domains cells.

Язык: Английский

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The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Cancers, Год журнала: 2022, Номер 14(12), С. 2887 - 2887

Опубликована: Июнь 11, 2022

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed among men worldwide 2020, first North America Europe. Patients with localized disease usually respond well to first-line treatments, however, up 30% develop castration-resistant (CRPC), which is often metastatic, making this stage of incurable ultimately fatal. Over last years, interest has grown into extracellular matrix (ECM) stiffening as an important mediator diseases, including cancers. While process increasingly well-characterized breast cancer, a similar in-depth look at ECM lacking for cancer. In review, we scrutinize current state literature regarding its potential association progression castration resistance.

Язык: Английский

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A guide to ERK dynamics, part 2: downstream decoding

Biochemical Journal, Год журнала: 2023, Номер 480(23), С. 1909 - 1928

Опубликована: Дек. 1, 2023

Signaling by the extracellular signal-regulated kinase (ERK) pathway controls many cellular processes, including cell division, death, and differentiation. In this second installment of a two-part review, we address question how ERK exerts distinct context-specific effects on multiple processes. We discuss dynamics activity induce selective changes in gene expression programs, with insights from both experiments computational models. With focus single-cell biosensor-based studies, summarize four major functional modes for signaling tissues: adjusting size populations, gradient-based patterning, wave propagation morphological changes, diversification states. These operation are disrupted cancer other related diseases represent potential targets therapeutic intervention. By understanding dynamic mechanisms involved signaling, there is pharmacological strategies that not only simply inhibit ERK, but also restore patterns improve disease outcomes.

Язык: Английский

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Large-scale control over collective cell migration using light-activated epidermal growth factor receptors

Cell Systems, Год журнала: 2025, Номер 16(3), С. 101203 - 101203

Опубликована: Март 1, 2025

Язык: Английский

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Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation

Current Opinion in Cell Biology, Год журнала: 2023, Номер 84, С. 102217 - 102217

Опубликована: Авг. 11, 2023

Extracellular signal-regulated kinase (ERK) has been recognized as a critical regulator in various physiological and pathological processes. Extensive research elucidated the signaling mechanisms governing ERK activation via biochemical regulations with upstream molecules, particularly receptor tyrosine kinases (RTKs). However, recent advances have highlighted role of mechanical forces activating RTK–ERK pathways, thereby opening new avenues into mechanochemical interplay multicellular tissues. Here, we review force-induced cells propose possible mechanosensing underlying mechanoresponsive activation. We conclude that are not merely passive factors shaping tissues but also active regulators cellular pathways controlling collective cell behaviors.

Язык: Английский

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Emerging roles and mechanisms of ERK pathway mechanosensing

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(12)

Опубликована: Ноя. 10, 2023

The coupling between mechanical forces and modulation of cell signalling pathways is essential for tissue plasticity their adaptation to changing environments. Whilst the number physiological pathological relevant roles mechanotransduction has been rapidly expanding over last decade, studies have mostly focussing on a limited mechanosensitive pathways, which include instance Hippo/YAP/TAZ pathway, Wnt/β-catenin or stretch-activated channel Piezo. However, recent development spreading new live sensors provided insights into contribution ERK pathway in mechanosensing various systems, emerges now as fast modular pathway. In this review, we will document key vivo vitro examples that established clear link deformation, stress signalling, comparing timescale stress. We then discuss different molecular mechanisms proposed so far, epistatic mechanics discussing cellular parameters affecting signalling. finish by consequences mechanics, outlining how interplay instrumental self-organisation long-range cell-cell coordination.

Язык: Английский

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Independent control over cell patterning and adhesion on hydrogel substrates for tissue interface mechanobiology

iScience, Год журнала: 2023, Номер 26(5), С. 106657 - 106657

Опубликована: Апрель 12, 2023

Tissue boundaries and interfaces are engines of morphogenesis in vivo. However, despite a wealth micropatterning approaches available to control tissue size, shape, mechanical environment vitro, fine-scale spatial cell positioning within constructs remains an engineering challenge. To address this, we augment DNA "velcro" technology for selective patterning ssDNA-labeled cells on mechanically defined photoactive polyacrylamide hydrogels. Hydrogels bearing photopatterned single-stranded (ssDNA) features capture then co-functionalized with extracellular matrix (ECM) proteins support subsequent adhesion patterned tissues. ECM protein co-functionalization does not alter ssDNA pattern fidelity, capture, or hydrogel elastic stiffness. This approach enables mechanobiology studies measurements signaling activity at dynamic precise initial patterning. Combining velcro functionalization provides independent placement, adhesion, mechanics, constituting new tool studying biological programming multicellular interactions engineered

Язык: Английский

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