Inhibitor κB Kinase

Ratz, Paul H.

doi:10.1161/circresaha.113.301952

Cited by 3 publications

(1 citation statement)

References 29 publications

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“…While AMPK is conventionally thought to regulate mTOR activity in the context of cell growth, we did not detect any altered RAPTOR signaling (data not shown), consistent with other studies demonstrating non-growth related AMPK signaling (33). The repeated cycling of myosin light chain (MLC) phosphorylation and subsequent de-phosphorylation is essential for the perpetual lever-like action that myosin exhibits on F-actin fibers, allowing cells to contract, relax, and then migrate (38, 39). Activation of AMPK has been proposed to affect MLC activity by preventing the de-phosphorylation that occurs on the regulatory unit of MLC (40, 41).…”

Section: Resultsmentioning

confidence: 99%

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling

et al. 2015

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Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a bias of agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that non-migratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.

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Section: Resultsmentioning

confidence: 99%

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling

et al. 2015

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Multiscale imaging of basal cell dynamics in the functionally mature mammary gland

Stevenson

Vanwalleghem

Stewart

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The mammary epithelium is indispensable for the continued survival of more than 5,000 mammalian species. For some, the volume of milk ejected in a single day exceeds their entire blood volume. Here, we unveil the spatiotemporal properties of physiological signals that orchestrate the ejection of milk from alveolar units and its passage along the mammary ductal network. Using quantitative, multidimensional imaging of mammary cell ensembles from GCaMP6 transgenic mice, we reveal how stimulus evoked Ca2+ oscillations couple to contractions in basal epithelial cells. Moreover, we show that Ca2+-dependent contractions generate the requisite force to physically deform the innermost layer of luminal cells, compelling them to discharge the fluid that they produced and housed. Through the collective action of thousands of these biological positive-displacement pumps, each linked to a contractile ductal network, milk begins its passage toward the dependent neonate, seconds after the command.

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Multiscale activity imaging in mammary gland reveals how oxytocin enables lactation

Stevenson

Vanwallegham

Stewart

et al. 2019

Preprint

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25The mammary epithelium is indispensable for the continued survival of more than 5000 mammalian species. For some, the volume of milk ejected in a single day exceeds their entire blood volume. Here, we unveil the spatiotemporal properties of physiological signals that orchestrate milk ejection. Using quantitative, multidimensional imaging of mammary cell ensembles, we reveal how stimulus-evoked Ca 2+ oscillations couple to contraction in basal 30 epithelial cells. Moreover, we show that Ca 2+ -dependent contractions generate the requisite force to physically-deform the innermost layer of luminal cells, forcing them to discharge the fluid that they produced and housed. Through the collective action of thousands of these biological positivedisplacement pumps, each linked to a contractile ductal network, milk is delivered into the mouth of the dependent neonate, seconds after the command. 35One Sentence Summary: This study provides a window into the organization, dynamics and role of epithelial Ca 2+ responses in the organ principally responsible for sustaining neonatal life in mammals. 40 Main Text:The ability to visualize how a single living cell, in its native environment, translates an extracellular message into an intracellular signal to execute a defined task at the cell-level and cooperatively achieve a biological outcome at the organ-level is revolutionizing our understanding of multicellular systems. Such an approach has provided new insights into a range of biological 45 phenomena, including how plants defend against herbivory (1), how fish escape looming predators (2, 3) and how mammals store memories (4). The rational design and continued refinement of genetically-encoded Ca 2+ indicators (GECIs) has fueled these advances (5). However, the use of GECIs for in situ activity mapping in vertebrates, has largely remained an achievement of neuroscience, where neural activity is tightly-coupled to intracellular Ca 2+ ([Ca 2+ ]i) signaling (6). 50 Efforts to map activity networks in specific populations of non-excitable cells in other solid organs is lagging. Our understanding of how epithelial tissues function, for example, has principally arisen through analysis of isolated cells (often serially-propagated under physiologically-extraneous conditions), retrospective examination of fixed tissue and interrogation of genetic knockout 3 models (where biological function is inferred in the absence of physiological redundancy or 55 compensation).The mammary gland has a universal and indispensable role in mammalian offspring survival. In its functionally-mature state, it consists of an inner layer of luminal (milk-producing) epithelial cells and an outer layer of contractile basal epithelial cells (7). When young offspring suckle, 60 maternally-produced oxytocin (OT) binds to its cognate receptor (the OXTR, a Gq-linked Gprotein coupled receptor) on mammary basal cells, causing them to contract (8). A model, therefore, emerges where activity may be tightly-coupled to [Ca 2+ ]i in this organ (8-11), making functional ...

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Inhibitor κB Kinase

Cited by 3 publications

References 29 publications

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling

Multiscale imaging of basal cell dynamics in the functionally mature mammary gland

Multiscale activity imaging in mammary gland reveals how oxytocin enables lactation

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