Schematic model of the ethylene signaling pathway. In the absence of ethylene perception (left), the formation of functional ethylene receptors depends on a copper cofactor provided by the copper transporter RESPONSIVE TO ANTAGONIST1 (RAN1), as well as activation by REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1), which depends on cytochrome b5 (Cb5). The ethylene receptors (represented here by ETR1 and ERS1 homodimers) at the endoplasmic reticulum (ER) membrane are in a protein complex with downstream components EIN2 and CTR1. The receptors associate with and activate (by an undefined signaling mechanism) the CTR1 protein kinase domain (KD), which phosphorylates the EIN2 C-terminal domain. Phosphorylation prevents EIN2 from signaling, and EIN2 is targeted for 26S proteasomal degradation by F-box proteins ETHYLENE INSENSITIVE2 TARGETING PROTEIN1 (ETP1) and ETP2. Meanwhile, in the nucleus, the F-box proteins ETHYLENE INSENSITIVE3 BINDING F-BOX1 (EBF1) and EBF2 target the EIN3/EIL1 transcription factors for 26S proteasomal degradation (only EIN3 is shown), preventing induction of gene expression such that there is no ethylene response. Additionally, there is a postulated secondary pathway from the receptors involving autophosphorylation of the His by the receptor His kinase (HK) domain, and transfer of the phosphate to the receiver (R) domain, followed by transfer of the phosphate to ARABIDOPSIS HIS PHOSPHOTRANSFER (AHP), which is released by a conformational change in the receptors (indicated by the altered shapes of the HK and R domains between the left and right sides) when they bind ethylene (right). The binding of ethylene (right) inactivates ethylene receptor signaling (indicated by the altered shapes of the HK and R domains between the left and right sides). In addition, the levels of ERS1 and other ethylene receptor isoforms (not shown) increase (represented by the darker color on the right side relative to the left side) due to transcriptional induction, but reach an equilibrium state due to being degraded by the 26S proteasome. CTR1 levels increase in the complex as well (represented by the darker color on the right side relative to the left side) due to the increased level of ethylene receptors and protect the ETR1 receptor from proteolysis. However, the ethylene receptors no longer activate CTR1, and therefore, EIN2 is no longer phosphorylated. Instead, a cytoplasmic portion of EIN2 is proteolytically cleaved by an unidentified protease, and the liberated C-terminal portion of EIN2 (C-END) moves into the nucleus where signal transmission results in EIN2-dependent 26S proteasomal degradation of the F-box proteins EBF1/2 and, consequently, the stabilization and accumulation of master transcription factors EIN3/EIL1. EIN3/EIL1 activate a transcriptional cascade that includes the downstream ERF1 transcription factor gene. An exoribonuclease (EXORIBONUCLEASE4 [XRN4]) also plays an indirect role in the repression of EBF1/2 mRNA.