ArticleThe Journal of biological chemistry2011
Essential role of endocytosis of the type II transmembrane serine protease TMPRSS6 in regulating its functionality.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- Development of Radioligand Therapy-Responsive Syngeneic Prostate Models through Murine Prostate-Specific Membrane Antigen Point Mutation.ACS pharmacology & translational science · 2026Article
- Type II Transmembrane Serine Proteases as Modulators in Adipose Tissue Phenotype and Function.Biomedicines · 2023Review
- Article
- Secretases Related to Amyloid Precursor Protein Processing.Membranes · 2021Review
- The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin.The Journal of biological chemistry · 2019Article
- Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines.Scientific reports · 2018Article
- Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities.Journal of cellular and molecular medicine · 2018Article
- Knockdown of TMPRSS3, a Transmembrane Serine Protease, Inhibits Proliferation, Migration, and Invasion in Human Nasopharyngeal Carcinoma Cells.Oncology research · 2018Article
- Proteolytic cleavages in the extracellular domain of receptor tyrosine kinases by membrane-associated serine proteases.Oncotarget · 2017Article
- Low intracellular iron increases the stability of matriptase-2.The Journal of biological chemistry · 2015Article
- N-glycosylation is required for matriptase-2 autoactivation and ectodomain shedding.The Journal of biological chemistry · 2014Article
- Identification and characterization of a novel murine allele of Tmprss6.Haematologica · 2013Article
- Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage.The Journal of biological chemistry · 2012Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The type II transmembrane serine protease TMPRSS6 (also known as matriptase-2) controls iron homeostasis through its negative regulation of expression of hepcidin, a key hormone involved in iron metabolism. Upstream of the hepcidin-regulated signaling pathway, TMPRSS6 cleaves its target substrate hemojuvelin (HJV) at the plasma membrane, but the dynamics of the cell-surface expression of the protease have not been addressed. Here, we report that TMPRSS6 undergoes constitutive internalization in transfected HEK293 cells and in two human hepatic cell lines, HepG2 and primary hepatocytes, both of which express TMPRSS6 endogenously. Cell surface-labeled TMPRSS6 was internalized and was detected in clathrin- and AP-2-positive vesicles via a dynamin-dependent pathway. The endocytosed TMPRSS6 next transited in early endosomes and then to lysosomes. Internalization of TMPRSS6 is dependent on specific residues within its N-terminal cytoplasmic domain, as site-directed mutagenesis of these residues abrogated internalization and maintained the enzyme at the cell surface. Cells coexpressing these mutants and HJV produced significantly decreased levels of hepcidin compared with wild-type TMPRSS6 due to the sustained cleavage of HJV at the cell surface by TMPRSS6 mutants. Our results underscore for the first time the importance of TMPRSS6 trafficking at the plasma membrane in the regulation of hepcidin expression, an event that is essential for iron homeostasis.
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