Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2

Maurer, Eva; Gütschow, Michael; Stirnberg, Marit

doi:10.1042/bj20121518

Cited by 25 publications

(33 citation statements)

References 46 publications

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“…However, this does not rule out the involvement of other molecules in this process. For example, a recent study showed that the hepatocyte growth factor activator inhibitor-2 (HAI-2), a serine protease inhibitor, can form a complex with MT2 to inhibit its enzymatic activity, which indirectly increases the hepcidin expression in hepatic cell lines (48). HAI-2 is a type I transmembrane glycoprotein with two Kunitz-type serine protease domains in their extracellular portion (49 -52).…”

Section: Discussionmentioning

confidence: 99%

Low Intracellular Iron Increases the Stability of Matriptase-2

Zhao

Nizzi

Anderson

et al. 2015

Journal of Biological Chemistry

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Background: Matriptase-2 (MT2) is essential for iron homeostasis. The mechanism for its regulation is controversial. Results: The cytoplasmic domain of MT2 is necessary for its stabilization by iron depletion. MT2 expression is not regulated at either the transcriptional mRNA or translational level by iron. Conclusion: Depletion of cellular iron stabilizes MT2. Significance: Low iron levels in hepatocytes stabilize MT2 to suppress hepcidin expression.

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Section: Discussionmentioning

confidence: 99%

Low Intracellular Iron Increases the Stability of Matriptase-2

Zhao

Nizzi

Anderson

et al. 2015

Journal of Biological Chemistry

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“…With 35% identity and structural similarities with matriptase-1 (Velasco et al, 2002), it is possible that matriptase-2 is also associated with an endogenous inhibitor. Indeed, Maurer et al (2013) recently demonstrated that HAI-2 is a cognate inhibitor of matriptase-2 that inhibits its proteolytic activity, and thus increases hepcidin expression in vitro . However, the physiological role of HAI-2 in the regulation of hepcidin and iron metabolism remains to be investigated.…”

Section: Biochemistry Of Matriptase-2mentioning

confidence: 99%

The role of TMPRSS6/matriptase-2 in iron regulation and anemia

2014

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Matriptase-2, encoded by the TMPRSS6 gene, is a member of the type II transmembrane serine protease family. Matriptase-2 has structural and enzymatic similarities to matriptase-1, which has been implicated in cancer progression. Matriptase-2 was later established to be essential in iron homeostasis based on the phenotypes of iron-refractory iron deficiency anemia identified in mouse models as well as in human patients with TMPRSS6 mutations. TMPRSS6 is expressed mainly in the liver and negatively regulates the production of hepcidin, the systemic iron regulatory hormone. This review focuses on the current understanding of matriptase-2 biochemistry, and its role in iron metabolism and cancer progression. In light of recent investigations, the function of matriptase-2 in hepcidin regulation, how it is being regulated, as well as the therapeutic potential of matriptase-2 are also discussed.

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“…Other groups report that the transcription of the MT2-encoding gene TMPRSS6 can be upregulated either by BMP6 through the BMPsignaling pathway (55) or by hypoxia through both HIF-1α and HIF-2α (56,57). Additionally, a recent study showed that hepatocyte growth factor activator inhibitor type 2 (HAI-2) can form a complex with MT2 to inhibit the enzymatic activity of MT2, which indirectly influences the expression of hepatic hepcidin (58). Despite these important observations, the precise mechanism for the regulation of MT2 expression by iron remains to be elucidated.…”

Section: Control Of Hepcidin Expressionmentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

195

158

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Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

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Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2

Cited by 25 publications

References 46 publications

Low Intracellular Iron Increases the Stability of Matriptase-2

Low Intracellular Iron Increases the Stability of Matriptase-2

The role of TMPRSS6/matriptase-2 in iron regulation and anemia

Iron regulation by hepcidin

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