A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins

The aryl hydrocarbon (Ah) receptor (AhR) is a member of the basic helix-loop-helix PER-ARNT-SIM (PAS) transcription factor family. Consistent with the notion that PAS proteins are biological sensors, AhR binding to Ah toxicants induces or represses transcription of a wide range of genes and results in a cascade of toxic responses. However, an endogenous role for AhR in development and homeostasis is supported by (1) the discovery of low affinity, endogenous ligands; (2) studies demonstrating a role for the receptor in development of liver and vascular systems, that were established using mice lacking AhR expression; and (3) the presence of functional dioxin-responsive elements in promoter regions of genes involved in cellular growth and differentiation. A large body of recent literature has implicated AhR in multiple signal transduction pathways. AhR is known to interact with signaling pathways that are mediated by estrogen receptor and other hormone receptors, hypoxia, nuclear factor κB, and retinoblastoma protein. In addition, AhR complexes may affect cellular signaling through interactions with various other regulatory and signaling proteins, including PAS heterodimerization partners (ARNT), chaperone and immunophilin-like proteins (e.g. HSP90, XAP2/ARA9/AIP, p23), protein kinases and phosphatases (e.g. tyrosine kinases, casein kinase 2, protein kinase C), and coactivators (e.g. SRC-1, RIP 140, CBP/p300). Here we summarize the types of molecular cross talk that have been identified between AhR and cell signaling pathways.