Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Truong, Thu H.; Ung, Peter M.U.; Palde, Prakash B.; Paulsen, Candice E.; Schlessinger, Avner; Carroll, Kate S.

doi:10.1016/j.chembiol.2016.05.017

Cited by 115 publications

(136 citation statements)

References 66 publications

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“…Thus, the joining of components of dedicated signaling networks together by microdomains might represent one way in which nearby effectors are modified and signals are passed from the ROS source in a concentration-dependent gradient. This model is in agreement with the recent discovery of oxidative PTMs of intracellular domains of cell surface receptors in animals (Truong et al, 2016). Conceptually, the hypothesis of local ROS maxima is well established, but the proposed model does not provide a sufficient explanation for the problem of differentiation between intracellular and apoplastic ROS sources.…”

Section: Intracellular Sensing Of Apoplastic Rossupporting

confidence: 77%

Bound by Fate: The Role of Reactive Oxygen Species in Receptor-Like Kinase Signaling

et al. 2017

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In plants, receptor-like kinases (RLKs) and extracellular reactive oxygen species (ROS) contribute to the communication between the environment and the interior of the cell. Apoplastic ROS production is a frequent result of RLK signaling in a multitude of cellular processes; thus, by their nature, these two signaling components are inherently linked. However, it is as yet unclear how ROS signaling downstream of receptor activation is executed. In this review, we provide a broad view of the intricate connections between RLKs and ROS signaling and describe the regulatory events that control and coordinate extracellular ROS production. We propose that concurrent initiation of ROS-dependent and -independent signaling linked to RLKs might be a critical element in establishing cellular responses. Furthermore, we discuss the possible ROS sensing mechanisms in the context of the biochemical environment in the apoplast. We suggest that RLK-dependent modulation of apoplastic and intracellular conditions facilitates ROS perception and signaling. Based on data from plant and animal models, we argue that specific RLKs could be components of the ROS sensing machinery or ROS sensors. The importance of the crosstalk between RLK and ROS signaling is discussed in the context of stomatal immunity. Finally, we highlight challenges in the understanding of these signaling processes and provide perspectives for future research.

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Section: Intracellular Sensing Of Apoplastic Rossupporting

confidence: 77%

Bound by Fate: The Role of Reactive Oxygen Species in Receptor-Like Kinase Signaling

et al. 2017

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“…This could have direct consequences for EGFR signaling as it is highly subject to redox regulation. Indeed, various recent studies indicated that oxidation of a conserved cysteine near the ATP-binding site within the EGFR tyrosine kinase domain, C797, is susceptible to oxidation, and research by Kate Carroll and co-workers has indicated that oxidation of EGFR C797 to a sulfenic acid (−SOH) in response to ligand stimulation contributes to enhanced tyrosine kinase activity [236–238]. Moreover, the extent of EGFR C797 oxidation varied between cancer cells with WT EGFR or containing oncogenic mutants (e.g.…”

Section: Duox1 Silencing Emt and Altered Egfr Dynamics: A Dangerousmentioning

confidence: 99%

“…In addition to oxidation to −SOH, our recent studies show that EGFR is also subject to S -glutathionylation, which may not necessarily affect kinase activity [134, 148, 239] but likely impact on the efficacy of EGFR TKI that are covalently targeted to C797 in an attempt to overcome TKI resistance[238, 240, 241]. Although oxidation of EGFR C797 to −SOH may enhance tyrosine kinase activity [148, 238], the significance of other modifications (e.g. S -glutathionylation) for EGFR regulation is unknown, and it is plausible that these redox modifications might also affect subcellular EGFR trafficking.…”

Section: Duox1 Silencing Emt and Altered Egfr Dynamics: A Dangerousmentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

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Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities.

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“…In fact, the “concentrations” of H 2 O 2 or a given protein target within a signaling complex is impossible to define without knowledge of the “volume” in which H 2 O 2 is allowed to diffuse, but are likely much greater than estimated cellular concentrations of specific proteins, or even the highest estimates of steady-state cellular H 2 O 2 concentrations (e.g. [24]), and will enable even kinetically less favorable reactions.…”

Section: Reaction Of H2o2 With Thiol Proteins: Reaction Kinetics Vmentioning

confidence: 99%

“…Since intermediate formation of Cys-SOH is being recognized as a functionally critically intermediate in redox-dependent regulation of e.g. tyrosine kinases [24, 25], it is important to reconcile this issue. In the following paragraphs, we will briefly discuss some of the concerns regarding the selectivity of certain derivatization strategies [26, 27], and point out important considerations with respect to extrapolating experimental findings from biochemical kinetic studies with isolated proteins conducted in the test tube to intact cellular contexts.…”

Section: Introductionmentioning

confidence: 99%

The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies

Heppner

Janssen–Heininger

Vliet

2017

Archives of Biochemistry and Biophysics

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The reversible oxidation of protein cysteine residues is well recognized as an important regulatory mechanism in redox-dependent cell signaling. Cysteine oxidation is diverse in nature and involves various post-translational modifications (sulfenic acids, disulfides, etc.) and the specific functional or structural impact of these specific oxidative events is still poorly understood. The proximal product of protein cysteine oxidation by biological reactive oxygen species (ROS) is sulfenic acid (Cys-SOH), and experimental evidence is accruing for the formation of Cys-SOH as intermediate in protein cysteine oxidation in various biological settings. However, the plausibility of protein Cys-SH oxidation by ROS has often been put in question because of slow reaction kinetics compared to more favorable reactions with abundant thiol-based reductants such as peroxiredoxins (Prx) or glutathione (GSH). This commentary aims to address this controversy by highlighting the unique physical properties in cells that may restrict ROS diffusion and allow otherwise less favorable cysteine oxidation of proteins. Some limitations of analytical tools to assess Cys-SOH are also discussed. We conclude that formation of Cys-SOH in biological systems cannot always be predicted based on kinetic analyses in homogenous solution, and may be facilitated by unique structural and physical properties of Cys-containing proteins within e.g. signaling complexes.

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Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Cited by 115 publications

References 66 publications

Bound by Fate: The Role of Reactive Oxygen Species in Receptor-Like Kinase Signaling

Bound by Fate: The Role of Reactive Oxygen Species in Receptor-Like Kinase Signaling

Paradoxical roles of dual oxidases in cancer biology

The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies

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