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Heterodimerization of SLC30A10/ZnT10 and SLC30A3/ZnT3 Modulates ERK1/2 Activity
Author(s) -
Zhao Yitong,
Feresin Rafaela G.,
FalconPerez Juan Manuel,
Salazar Gloria
Publication year - 2016
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.30.1_supplement.878.7
Subject(s) - endosome , microbiology and biotechnology , phosphorylation , chemistry , signal transduction , tyrosine , protein kinase b , biochemistry , immunoprecipitation , intracellular , tyrosine kinase , cell fractionation , cell growth , biology , enzyme , gene
Zinc is an essential micronutrient required for metabolic function, but high concentration of zinc is toxic. The solute carrier 30A (SLC30A) family of zinc exporters transports zinc into the lumen of intracellular organelles in order to prevent zinc toxicity. We reported that the formation of tyrosine dimers is required for zinc transporter 3 (ZnT3) activity and targeting to synaptic‐like micro‐vesicles (SLMVs) in PC12 cells, as well as the formation of ZnT3/ZnT10 heterodimers. Here, we focus on ZnT10 to determine the role of heterodimerization in the sorting of ZnTs in the endosomal/lysosomal pathway. Using cell fractionation, immunoprecipitation and immunofluorescence approaches, we found that ZnT10 resides in transferrin receptor (TfR) and Ras‐related protein 5 (Rab5) positive endosomes and forms covalent heterodimers and oligomers with ZnT3. The interaction of ZnT10 with ZnT3 is mediated by dityrosine bonds and was required to increase the phosphorylation of extracellular signal regulated kinase (ERK1/2), but not Akt, in response to epidermal growth factor (EGF), a regulator of cell growth, proliferation, and differentiation. Further, mutation of tyrosine 4 in ZnT10 reduced ZnT3/ZnT10 dityrosine‐mediated heterodimerization, and ERK1/2 phosphorylation by EGF. We propose that ZnT10 and zinc play a role in signal transduction, which is mediated by homo and heterodimerization with other ZnTs, and that ZnT3/ZnT10 heterodimer could be a potential therapeutic target to regulate cell proliferation during tumorigenesis.