Outlines of the AhR signaling pathway

Outlines of the AhR signaling pathway. a) Inactive AhR is cytosolic and forms a complex together with chaperone proteins HSP90, Src, AIP, and p23. Binding between AhR and its ligand translocates the activated ligand-AhR complex into the nucleus, where it dissociates from its chaperone proteins. The complex heterodimerizes with AhR Nuclear Translocator (ARNT) and binds to Xenobiotic-Responsive Elements (XRE) in the promoter regions of target genes [173], enabling modulation of target gene expression by inducing mRNA transcription. Some target genes include CYP1A1, CYP1A2, CYP1B1, NAD(P)H quinone dehydrogenase 1 (NQO1), glutathione s-transferase (GST), UDP-Glucuronosyltransferase (UGT), and aryl hydrocarbon receptor repressor (AhRR). AhRR suppresses AhR activity through binding with ARNT and XRE [174-176]. b) Following exposure to a highly carcinogenic ligand, like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), intracellular calcium concentrations increase, sourced extracellularly and from the endoplasmic reticulum [173]. TCDD induces functional activation of tyrosine kinase Src which is released from the AhR complex [177], altering cellular adhesion properties in the process by activating focal adhesion kinase (FAK) [177]. Calcium influx activates protein kinase C (PKCα) which phosphorylates phospholipase A2 (cPLA2), stimulating the production of arachidonic acid [173]. Src activation also activates mitogen-activated protein kinases (MAPK), ERK-1 and –2, allowing the transcription of cyclooxygenase-2 (COX2) which utilizes arachidonic acid to produce prostaglandins, ultimately modifying pathophysiological process like inflammation [173,178]. (Created with BioRender.com)

Publication

Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs (2024) Francoise Congues, et al. Biochem Pharmacol. 2024 May 24;223(NA). Figure: F1. Homo sapiens

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