ABSTRACT The ciliate Euplotes raikovi produces a family of diffusible signal proteins (pheromones) that function as prototypic growth factors. They may either promote cell growth, by binding to pheromone receptors synthesized by the same cells from which they are secreted (autocrine activity), or induce a temporary cell shift from the growth stage to a mating (sexual) one by binding to pheromone receptors of other, conspecific cells (paracrine activity). In cells constitutively secreting the pheromone E r -1, it was first observed that the expression of the E r -1 receptor “p15,” a type II membrane protein of 130 amino acids, is quantitatively correlated with the extracellular concentration of secreted pheromone. p15 expression on the cell surface rapidly and markedly increased after the removal of secreted E r -1 and gradually decreased in parallel with new E r -1 secretion. It was then shown that p15 is internalized through endocytic vesicles following E r -1 binding and that the internalization of p15/E r -1 complexes is specifically blocked by the paracrine p15 binding of E r -2, a pheromone structurally homologous to, and thus capable of fully antagonizing, E r -1. Based on previous findings that the p15 pheromone-binding site is structurally equivalent to E r -1 and that E r -1 molecules polymerize in crystals following a pattern of cooperative interaction, it was proposed that p15/E r -1 complexes are internalized as a consequence of their unique property (not shared by p15/E r -2 complexes) of undergoing clustering.