In addition, there are many examples of steroid receptor
mutations that confer ligand-independent constitutive activity
(36–40). At least one of these, at position 537 of the human
ER, occurs during the evolution of mammary tumor cells in
humans (41). Intriguingly, the Octopus ER is not conserved
with the human ER or the ancestral steroid receptor at two
of these positions, L536F and Y537C (based on human numbering).
These replacements may contribute to the mechanism
by which constitutive activity was likely to have been
gained in the mollusk ERs. In addition, the loss of H524 from
the ancestor may be important for the loss of estradiol binding
in the mollusk ERs. The frequency and structural simplicity
by which liganded receptors have evolved constitutive
activation provides some evidence against the ancestral
orphan receptor theory and favors the view that constitutive
activation has evolved several times in parallel from a liganddependent
nuclear receptor ancestor.