Epiregulin and EGFR interactions are involved in pain processing

Martin, Loren J.; Smith, Shad B.; Khoutorsky, Arkady; Magnussen, Claire; Samoshkin, Alexander; Sorge, Robert E.; Cho, Chulmin; Yosefpour, Noosha; Sivaselvachandran, Sivaani; Tohyama, Sarasa; Cole, Tiffany; Khuong, Thang M.; Mir, Ellen; Gibson, Dustin G.; Wieskopf, Jeffrey S.; Sotocinal, Susana G.; Austin, Jean-Sébastien; Meloto, Carolina B.; H., Gitt, Joseph; Gkogkas, Christos G.; Sonenberg, Nahum; Greenspan, Joel D.; Fillingim, Roger B.; Ohrbach, Richard; Slade, Gary D.; Knott, Charles; Dubner, Ronald; Nackley, Andrea G.; Ribeiro‐da‐Silva, Alfredo; Neely, G. Gregory; Maixner, William; Zaykin, Dmitri V.; Mogil, Jeffrey S.; Diatchenko, Luda

doi:10.1172/jci87406

Cited by 89 publications

(132 citation statements)

References 52 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…An intriguing theme emerging from these distinct interactomes is the prominence of epidermal growth factor receptor (EGFR) ligands as possible mediators of interactions between diseased tissue and mouse and human nociceptors. This finding is consistent with recent preclinical and clinical findings suggesting efficacy of blocking EGFR signaling for chronic pain (Kersten et al, 2013;Kersten et al, 2015;Martin et al, 2017;Kersten et al, 2019).…”

Section: Introductionsupporting

confidence: 92%

“…Previous studies have implicated the EGFR pathway with chronic pain. Genetic associations studies link the EGFR and the EGFR ligand EREG chronic temporomandibular joint pain (Martin et al, 2017). Animal pain models suggest that EGFR activation by epiregulin encoded by the EREG gene promotes inflammatory and neuropathic pain and that EGFR signaling is critical for pain promoting effects of opioids (Martin et al, 2017;Puig et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of the EGFR pathway in chronic pain has been previously noted in the literature, but not in the context of RA pain. For instance, EREG-mediated EGFR activation causes pain sensitization through PI3K/AKT/mTOR pathways in inflammatory pain models (Martin et al, 2017) and EGFR inhibition reduces opioid tolerance and hyperalgesia (Puig et al, 2020). Moreover, EGFR inhibitors have recently been used successfully for the treatment of neuropathic pain in patients (Kersten et al, 2015;Kersten et al, 2019).…”

Section: Disease Promoting Macrophages From Rheumatoid Arthritis Patimentioning

confidence: 99%

See 2 more Smart Citations

A pharmacological interactome platform for discovery of pain mechanisms and targets

Wangzhou

Paige

Neerukonda

et al. 2020

Preprint

View full text Add to dashboard Cite

Smith for help with the colonic single neuron sequencing data, Dr. Brian Gulbransen and lab for help with the enteric glia TRAP data and Dr. Zhenyu Xuan for clarifying TCGA metadata formats. We thank all the authors of the papers from which we used their sequencing data for their exemplary transparency in sharing the details of their work with us. AbstractCells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naïve and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligandreceptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.In this formula stands for distance, and stands for gene expression level across all cells in the first condition and second condition respectively, stands for standard deviation and stands for mean.

show abstract

Section: Introductionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Disease Promoting Macrophages From Rheumatoid Arthritis Patimentioning

confidence: 99%

See 1 more Smart Citation

A pharmacological interactome platform for discovery of pain mechanisms and targets

Wangzhou

Paige

Neerukonda

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…While there is clear evidence that NGF and IL-6, among other pain-promoting molecules, can activate signaling pathways upstream of translation, a new mechanism by which mTORC1 is stimulated in nociceptors in acute and chronic pain conditions has been recently suggested: the EGFR [8]. This transmembrane receptor from the tyrosine kinase family is activated in neuropathic and chronic inflammation pain models.…”

Section: Eif4e Integrates Inputs From the Mapk And Mtor Pathways To Mmentioning

confidence: 99%

“…The potential role of EGFR gene polymorphism in humans has been assessed in several cohorts of patients with temporomandibular disorder (TMD), where a correlation between single nucleotide polymorphisms (SNPs) in EGFR and the incidence of TMD has been identified. Finally, studies in both humans and mice demonstrated that expression levels of epiregulin (EREG), an endogenous agonist of EGFR, are significantly increased in persistent pain conditions [8] and several clinical case reports suggest a role of EGFR in cancer pain [56,57]. Therefore, these studies collectively support a model wherein elevated levels of EREG lead to the stimulation of EGFR and its major downstream effector, mTORC1, to promote the translation of MMP9 and potentially other mRNAs that are involved in promoting pain hypersensitivity.…”

Section: Eif4e Integrates Inputs From the Mapk And Mtor Pathways To Mmentioning

confidence: 99%

Translational Control Mechanisms in Persistent Pain

Khoutorsky

Price

2018

Trends in Neurosciences

Self Cite

100

114

View full text Add to dashboard Cite

Persistent pain, which is poorly treated and estimated to afflict one third of the world’s population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics.

show abstract

Functional suppression of Epiregulin impairs angiogenesis and aggravates left ventricular remodeling by disrupting the extracellular‐signal‐regulated kinase1/2 signaling pathway in rats after acute myocardial infarction

Cai

Xie

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

Acute myocardial infarction (AMI), a severe consequence of coronary atherosclerotic heart disease, is often associated with high mortality and morbidity. Emerging evidence have shown that the inhibition of the extracellular‐signal‐regulated kinase (ERK) signaling pathway appears to protect against AMI. Epiregulin (EREG) is an autocrine growth factor that is believed to activate the MEK/ERK signaling pathway. Therefore, the aim of the present study was to determine the expression patterns of EREG in AMI and to further study its effects on AMI induced experimentally in rats focusing on angiogenesis and left ventricular remodeling. Microarray‐based gene expression profiling of AMI was used to identify differentially expressed genes. To understand the biological significance of EREG and whether it is involved in AMI disease through the ERK1/2 signaling pathway, rats after AMI were treated with small interfering RNA (siRNA) against EREG, an ERK1/2 pathway inhibitor, PD98059, or both of them. The microarray data sets GSE66360 and GSE46395 showed that EREG was robustly induced in AMI. Both siRNA‐mediated depletion of EREG and PD98059 treatment were shown to significantly increase infarct size and left ventricular cardiomyocyte loss and enhance left ventricular remodeling. In addition, we also found that the ERK1/2 signaling pathway was inhibited following siRNA‐mediated EREG inhibition and PD98059 could enhance the effects of EREG inhibition on AMI. In conclusion, these findings highlight that the silencing of EREG inhibits angiogenesis and promotes left ventricular remodeling by disrupting the ERK1/2 signaling pathway, providing a novel therapeutic target for limiting AMI.

show abstract

Epiregulin and EGFR interactions are involved in pain processing

Abstract: that involves TRPV1, the PI3K/AKT/mTOR/4E-BP1 signaling pathway, and MMP-9, a molecule known to be involved in inflammation and the early stages of chronic pain (18).

Cited by 89 publications

References 52 publications

A pharmacological interactome platform for discovery of pain mechanisms and targets

A pharmacological interactome platform for discovery of pain mechanisms and targets

Translational Control Mechanisms in Persistent Pain

Functional suppression of Epiregulin impairs angiogenesis and aggravates left ventricular remodeling by disrupting the extracellular‐signal‐regulated kinase1/2 signaling pathway in rats after acute myocardial infarction

Contact Info

Product

Resources

About