Since antibody against to nuclear ER was directly bound to membrane ER, much evidence favor the idea that membrane ER is the same protein as nuclear receptor, transported to the plasma membrane by unclear mechanisms (Pappas et al. 1995). Moreover, the membrane ER interacts with several membrane–bound molecule including PI–3K and Ras (an adaptor protein of MAPK pathway) (Simoncini et al. 2003), which contribute to intracellular signaling activations.