HER1 acts as a central mediator for multiple signaling pathways. A variety of extracellular ligands trigger the phosphorylation of HER1 on Tyr 845. These include the following: thrombin, endothelin, and LPA, which bind G-protein coupled receptors; growth hormone, which binds a cytokine receptor; and estrogen, which binds a steroid hormone receptor. Moreover, c-Src kinase activity is required for the ability of LPA, endothelin, growth hormone, and estrogen to induce phosphorylation of Tyr 845. We hypothesize that c-Src-mediated phosphorylation of Tyr 845 is a central signaling event and is required for mitogenesis to occur in response to a variety of external stimuli in addition to EGF. The signaling molecules that transmit mitogenic cues from phosphorylated Tyr 845 have yet to be delineated, but may include such effectors as STAT5b, PI-3K, or ERK5. ER, estrogen receptor.