(A) Classical genomic signaling. E2 binds ER in the cytoplasm or in the nucleus to mediate translocation, dimerization, and association of ERs to gene regulatory regions known as estrogen response elements (EREs). (B) Indirect genomic signaling (non-classical activation). Binding of growth factors (GFs) to growth factor receptors (GFRs) such as IGF-1R can activate PI3K and MAPK signaling pathways that in turn can phosphorylate ERs in the cytoplasm. The phosphorylated ERs translocate to the nucleus where they tether with other transcription factors on non-ERE sites (i.e. transcription factor response elements, TFREs) to modulate transcription of genes lacking EREs. The phosphorylated ER can also dimerize with ligand-bound ER to further modulate transcription or (C) bind to EREs in the absence of ligands to mediate gene-transcription. (D) Non-genomic signaling. E2 can bind to ERs in the cytoplasm (or at the plasma membrane) which directly interact with Src that modulates PI3K and MAPK signaling. In addition, E2 can bind the membrane bound GPER1 which also modulates kinase activations, either in a Src-mediated way or by stimulating adenylyl cyclase and cAMP production, which in turn can modulate different transcription factor activations, as well as phosphorylation of Ca²⁺ channels and influx of Ca²⁺. E2 binding to GPER1 can also activate the phospholipase C (PLC) pathway and mobilization of intracellular Ca²⁺ stores. This Ca²⁺ mobilization results in rapid non-genomic effects, adapting the cell to immediate responses, whereas the genomic signaling is slower, adapting the cell to long-term effects.