Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS

Chatterjee, Shampa; Browning, Elizabeth Anne; Hong, Nankang; Debolt, Kristine; Sorokina, Elena M.; Liu, Weidong; Birnbaum, Morris J.; Fisher, Aron B.

doi:10.1152/ajpheart.00298.2011

Cited by 126 publications

(133 citation statements)

References 47 publications

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“…It also has been shown that membrane depolarization activates PI3K signaling and AKT phosphorylation in epithelial cells (45). Our findings that knockdown of ANO1 or its inhibition by CaCCinh-A01 decreases chloride channel activity suggest that ANO1 activates EGFR phosphorylation via imbalanced intracellular ion homeostasis, membrane depolarization, and/or activation of further ion channels.…”

Section: Ano1 Regulates Egfr-and Calcium-dependent Signaling Pathwayssupporting

confidence: 57%

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Britschgi

Bill

Brinkhaus

et al. 2013

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

269

373

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The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.ion channel | CaCCinh-A01 | TMEM16A | HNSCC | ESCC

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Section: Ano1 Regulates Egfr-and Calcium-dependent Signaling Pathwayssupporting

confidence: 57%

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Britschgi

Bill

Brinkhaus

et al. 2013

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

269

373

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“…Probably the fastest injury-induced signals are bioelectric in nature. Exogenous EF activate NADPH oxidases in cells in vitro (Chatterjee et al, 2012;Li et al, 2013). Thus, we propose that endogenous EF activate NADPH oxidases (Fig.…”

Section: Towards a Comprehensive Model Of Redox And Bioelectric Integmentioning

confidence: 80%

Early bioelectric activities mediate redox-modulated regeneration

et al. 2016

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Reactive oxygen species (ROS) and electric currents modulate regeneration; however, the interplay between biochemical and biophysical signals during regeneration remains poorly understood. We investigate the interactions between redox and bioelectric activities during tail regeneration in Xenopus laevis tadpoles. We show that inhibition of NADPH oxidase-mediated production of ROS, or scavenging or blocking their diffusion into cells, impairs regeneration and consistently regulates the dynamics of membrane potential, transepithelial potential (TEP) and electric current densities (J I ) during regeneration. Depletion of ROS mimics the altered TEP and J I observed in the non-regenerative refractory period. Short-term application of hydrogen peroxide (H 2 O 2 ) rescues (from depleted ROS) and induces (from the refractory period) regeneration, TEP increase and J I reversal. H 2 O 2 is therefore necessary for and sufficient to induce regeneration and to regulate TEP and J I . Epistasis assays show that voltage-gated Na + channels act downstream of H 2 O 2 to modulate regeneration. Altogether, these results suggest a novel mechanism for regeneration via redoxbioelectric orchestration.

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“…The artificial capillary system (FiberCell Systems, Frederick, MD) for flow adapting PMVEC has been described previously (5,6,8). Stop of flow was achieved by turning off the peristaltic pump to stop flow of culture medium over the cells; the cells, however, were fed by oxygenated medium from the side ports to ensure that lack of flow did not compromise oxygen and nutrient supply.…”

Section: Flow Adaptation Of Endothelial Cells and Cessation Of Flow Imentioning

confidence: 99%

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

Noel

Wang

Hong

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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AB, Chatterjee S. PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium. Am J Physiol Lung Cell Mol Physiol 305: L805-L818, 2013. First published September 27, 2013 doi:10.1152/ajplung.00123.2013.-We showed that stop of flow triggers a mechanosignaling cascade that leads to the generation of reactive oxygen species (ROS); however, a mechanosensor coupled to the cytoskeleton that could potentially transduce flow stimulus has not been identified. We showed a role for KATP channel, caveolae (caveolin-1), and NADPH oxidase 2 (NOX2) in ROS production with stop of flow. Based on reports of a mechanosensory complex that includes platelet endothelial cell adhesion molecule-1 (PECAM-1) and initiates signaling with mechanical force, we hypothesized that PECAM-1 could serve as a mechanosensor in sensing disruption of flow. Using lungs in situ, we observed that ROS production with stop of flow was significantly reduced in PECAM-1 Ϫ/Ϫ lungs compared with lungs from wild-type (WT) mice. Lack of PECAM-1 did not affect NOX2 activation machinery or the caveolin-1 expression or caveolae number in the pulmonary endothelium. Stop of flow in vitro triggered an increase in angiogenic potential of WT pulmonary microvascular endothelial cells (PMVEC) but not of PECAM-1 Ϫ/Ϫ PMVEC. Obstruction of flow in lungs in vivo showed that the neutrophil infiltration as observed in WT mice was significantly lowered in PECAM-1 Ϫ/Ϫ mice. With stop of flow, WT lungs showed higher expression of the angiogenic marker VEGF compared with untreated (sham) and PECAM-1 Ϫ/Ϫ lungs. Thus PECAM-1 (and caveolae) are parts of the mechanosensing machinery that generates superoxide with loss of shear; the resultant ROS potentially drives neutrophil influx and acts as an angiogenic signal. mechanotransduction; stop of flow; pulmonary endothelium; PECAM; K atp (Kir6.2) channel; NOX2; angiogenic potential CELLS SENSE THE PHYSICAL STIMULUS in their environment and translate these physical forces into biochemical signals (20, 37). Sensing and responding to a physical force require specialized structures and machinery that can engage in signal transduction (12,23,42).In the vascular system, with a highly distributed network of blood vessels, mechanical forces arising from blood flow initiate signaling that helps maintain vascular structure and function. Indeed, shear associated with blood flow is sensed by the endothelium and the resultant signaling regulates normal vascular physiology (such as embryonic morphogenesis and organization of the vascular tree) while irregular or abnormal shear can lead to vascular dysfunction and disease (19,27). Thus the mechanosignaling that accompanies various shear profiles and patterns, regular or aberrant, governs susceptibility to atherosclerosis, by inducing athero-protective or atheroprone phenotypes in endothelial cells (10,22). It thus becomes important to understand the link among the mechanical force, the shear sensing machinery and...

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Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS

Cited by 126 publications

References 47 publications

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Early bioelectric activities mediate redox-modulated regeneration

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium

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