Abstract
Classical estrogen, progesterone, and androgen receptors (ERs, PRs, and ARs) localize outside the nucleus at the plasma membrane of target cells. From the membrane, the receptors signal to activate kinase cascades that are essential for the modulation of transcription and nongenomic functions in many target cells. ER, PR, and AR trafficking to the membrane requires receptor palmitoylation by palmitoylacyltransferase (PAT) protein(s). However, the identity of the steroid receptor PAT(s) is unknown. We identified the DHHC-7 and -21 proteins as conserved PATs for the sex steroid receptors. From DHHC-7 and -21 knockdown studies, the PATs are required for endogenous ER, PR, and AR palmitoylation, membrane trafficking, and rapid signal transduction in cancer cells. Thus the DHHC-7 and -21 proteins are novel targets to selectively inhibit membrane sex steroid receptor localization and function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetyltransferases
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Acyltransferases / genetics
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Acyltransferases / metabolism*
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Animals
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CHO Cells
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Cell Line, Tumor
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Cricetinae
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Epigenesis, Genetic
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Estradiol / pharmacology
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Estradiol / physiology
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Estrogen Receptor alpha / metabolism*
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Gene Knockdown Techniques
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lipoylation
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MAP Kinase Signaling System
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Presenilin-2 / genetics
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Presenilin-2 / metabolism
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Protein Binding
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Protein Transport
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RNA Interference
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Receptors, Androgen / metabolism*
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Receptors, Progesterone / metabolism*
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Response Elements
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Transcription, Genetic
Substances
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ESR1 protein, human
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Estrogen Receptor alpha
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Intracellular Signaling Peptides and Proteins
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PSEN2 protein, human
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Presenilin-2
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Receptors, Androgen
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Receptors, Progesterone
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Estradiol
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Acyltransferases
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ZDHHC21 protein, human
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Acetyltransferases
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ZDHHC7 protein, human