An inherent role of microtubule network in the action of nuclear receptor

Estrogen receptor alpha (ER alpha) functions as both a transcription factor and a mediator of rapid estrogen signaling. Recent studies have shown a role for ER alpha-interacting membranous and cytosolic proteins in ER alpha action, but our understanding of the role of the microtubule network in the modulation of ER alpha signaling remains unclear. Here we found that enclogenous ER alpha associates with microtubules through the microtubule-binding protein hernatopok etic PBX-interaction protein (HPIP). Biochemical and RNA-interference studies demonstrated that HPIP influences ER alpha-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ER alpha, which in turn stimulates AKT and MAPK. We also found that ER alpha interacts with beta-tubulin through HPIP. Destabilization of microtubules activated ER alpha signaling, whereas stabilization of microtubules repressed ER alpha transcriptional activity in a HPIP-depenclent manner. These findings revealed a role for HPIPmicrotubule complex in regulating 17 beta-estradiol-ER alpha responses in mammalian cells and discovered an inherent role of microtubules in the action of nuclear receptor.