Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane.
Classical sex steroid receptors (SRs) localize at the plasma membranes (PMs) of cells, initiating signal transduction through kinase cascades that contribute to steroid hormone action. Palmitoylation of the SRs is required for membrane localization and function, but the proteins that facilitate this modification and subsequent receptor trafficking are unknown. Initially using a proteomic approach, we identified that heat shock protein 27 (Hsp27) binds to a motif in estrogen receptor alpha (ERalpha) and promotes palmitoylation of the SR. Hsp27-induced acylation occurred on the ERalpha monomer and augmented caveolin-1 interactions with ERalpha, resulting in membrane localization, kinase activation, and DNA synthesis in breast cancer cells. Oligomerization of Hsp27 was required, and similar results were found for the trafficking of endogenous progesterone and androgen receptors to the PMs of breast and prostate cancer cells, respectively. Small interfering RNA (siRNA) knockdown of Hsp27 prevented sex SR trafficking to and signaling from the membrane. These results identify a conserved and novel function for Hsp27 with potential as a target for interrupting signaling from membrane sex SRs to tumor biology in hormone-responsive cancers.
Razandi
Mahnaz
M
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, USA.
Pedram
Ali
A
Levin
Ellis R
ER
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054878:Lipoylation; D008297:Male; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D051242:Caveolin 1; D047628:Estrogen Receptor alpha; D055551:HSP27 Heat-Shock Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D011944:Receptors, Androgen