Figure 1.

Intracellular actions of mitogenic hormones. Estrogen (E₂) and epidermal growth factor (EGF) act on their respective receptors, estrogen receptor α (ERα), and EGF receptor (EGFR), to initiate crosstalk between extranuclear signaling pathways and their genomic programs. ERα indirectly and EGFR directly activate phospholipase C γ (PLCγ), resulting in cleavage of PIP₂ to DAG (diacylglycerol) and IP₃ (inositol triphosphate). IP₃ then binds to IP₃ receptors (IP₃Rs) in the endoplasmic reticulum (EnR) membrane, causing moderate efflux of calcium from the lumen of the EnR into the cell body. This calcium signal activates all three arms of the unfolded protein response (UPR) and acts as an authorizing signal for E₂-ERα and EGF-EGFR modulation of gene expression and cell proliferation. In parallel, E₂-ERα and EGF-EGFR modulate additional extranuclear signal transduction pathways, including activation of ERK and Akt signaling. Activation of these pathways is also important for subsequent cell proliferation and crosstalks with the E₂-ERα and EGF-EGFR genomic programs.