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Prolactin‐stimulated ubiquitination of the zinc transporter ZnT2 regulates zinc secretion
Author(s) -
Seo Young Ah,
Kelleher Shan L
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1067.4
Subject(s) - ubiquitin , secretion , microbiology and biotechnology , proteasome , chemistry , lysine , biochemistry , biology , gene , amino acid
Zinc (Zn), an essential divalent cation, is required for over 300 biological processes including DNA and protein synthesis and intracellular signaling. The Zn transporter ZnT2 regulates Zn export from mammary epithelial cells (MECs) into milk during lactation. Tight regulation of ZnT2 is critical to ensure adequate Zn transfer to the infant yet maintain Zn homeostasis in MECs. Prolactin (PRL) regulates nutrient production and secretion from MECs. PRL signaling is deactivated through ubiquitination and degradation of its receptor (PRLr). Herein, we report that after an initial increase, PRL decreased Zn secretion in endogenous and ZnT2‐overexpressing MECs. This resulted from ZnT2 internalization and ubiquitination, which targeted ZnT2 for proteasome‐dependent degradation. Mutagenesis identified two N‐terminal lysine residues (K 4 and K 6 ) necessary for ubiquitin attachment. Mutation of these lysine residues to arginine (K 4 R and K 6 R) inhibited ubiquitination and degradation, which confined ZnT2 to the cell membrane and maintained Zn secretion. These findings indicate that PRL‐mediated activation of ubiquitin‐dependent ZnT2 degradation represses Zn secretion from MECs. This suggests that PRL‐stimulated ubiquitination regulates ZnT2 function to maintain optimal cell function in mammary cells and provides insight into novel mechanisms through which ubiquitination regulates ion transport.