c-Src–Mediated Phosphorylation of NoxA1 and Tks4 Induces the Reactive Oxygen Species (ROS)–Dependent Formation of Functional Invadopodia in Human Colon Cancer Cells

Gianni, Davide; Taulet, Nicolas; DerMardirossian, Céline; Bokoch, Gary M.

doi:10.1091/mbc.e10-08-0685

Cited by 95 publications

(71 citation statements)

References 54 publications

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“…Also, ROS promote cancer progression by participating in oncogenic signaling pathways such as Ras, c-Myc and c-Src. [9][10][11] Indeed, Ras-induced ROS generation caused to increase the activation of mitogen-activated protein kinase (MAPK) and DNA-binding activities of the transcription factors such as activator protein-1, activator protein-2 and nuclear factor-kB in rat kidney epithelial cells, 12 suggesting that ROS participate in cell signaling.…”

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confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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“…The role of FLT3 in regulating both the normal migration of haematopoietic progenitors, as well as the subversive migration of leukaemic cells has been demonstrated (Fukuda and Pelus, 2006). There is evidence to suggest that FLT3 signalling involves downstream activation of Nox and subsequent increase in ROS levels (Reddy et al, 2011;Sallmyr et al, 2008a) and it has also been established that ROS produced by Nox can promote and stabilise the cell protrusions that facilitate migration and invasion Gianni et al, 2011). With regard to the mechanism whereby Nox-derived ROS exert their effects on the cytoskeletal machinery of the cell, much data support a role for Src kinase in translating the upstream oxidant generation to the downstream protein modifications and the resulting phenotypic effects.…”

Section: Discussionmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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“…These interacting partners includes adaptor proteins and actin regulatory proteins, such as NCK1, NCK2, GRB2, CTTN (Cortactin), WASL (N-WASP), ACTR2/ACTR3 (Arp2/3) complex, and ARHGAP35 (p190RhoGAP) (Crimaldi et al, 2009;Oikawa et al, 2008;Stylli et al, 2009). TKS5 also interacts with NOXA1 and CYBA (p22phox), which are components of the NADPH oxidase complex, and thereby promotes reactive oxygen species (ROS) production by NOX enzymes at invadosomes Gianni et al, 2010;. ROS have been shown to facilitate invadosome formation by maintaining or amplifying the phosphorylation of TKS5.…”

Section: Functionmentioning

confidence: 99%

SH3PXD2A (SH3 and PX domains 2A)

Li¹,

Jacks²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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The TKS5 protein, encoded by the gene SH3PXD2A, is a scaffolding protein essential for the formation of podosomes and invadopodia in untransformed cells and cancer cells, respectively. Podosomes and invadopodia (which collectively are termed invadosomes) are actin-rich cellular protrusions capable of secreting proteolytic enzymes that can degrade the extracellular matrix. These structures are thought to regulate cellular migration and invasion, as well as adhesion and the release of growth factors. In the context of cancer, TKS5-dependent invadopodia activity has been shown to play important roles in tumor growth and metastasis in various cancer types. Multiple isoforms of TKS5 exist due to alternative mRNA splicing and promoter usage.

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c-Src–Mediated Phosphorylation of NoxA1 and Tks4 Induces the Reactive Oxygen Species (ROS)–Dependent Formation of Functional Invadopodia in Human Colon Cancer Cells

Cited by 95 publications

References 54 publications

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

SH3PXD2A (SH3 and PX domains 2A)

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