# Roles of Neogenin and Matriptase-2 in Iron Homeostasis

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $678,029

## Abstract

Project Summary/Abstract
This proposal targets the molecular basis of iron overload disorders and iron-restricted anemia, which are
among the most common hematological diseases worldwide. Recent studies have documented the iron-
regulatory hormone hepcidin as the key molecule responsible for systemic iron homeostasis. Hepcidin
expression is induced via the bone morphogenetic protein (BMP)-signaling pathway and requires the
involvement of other key plasma membrane proteins, including hemojuvelin (HJV), hemochromatosis protein
(HFE), transferrin receptor-2 (TfR2), and neogenin (NEO1). Mutations in the HJV, HFE, or TfR2 genes in
humans reduce hepcidin expression and cause hereditary hemochromatosis. Conversely, matriptase-2 (MT2)
is a robust suppressor for hepcidin expression. Mutations in the MT2 gene in humans result in increased
hepcidin expression, which leads to iron-refractory iron-deficiency anemia. However, the precise mechanisms
by which neogenin (NEO1) induces, MT2 suppresses, and iron modulates hepcidin expression are poorly
understood. Our long-term goal is to understand the mechanism of systemic iron homeostasis. The objective of
this grant is to characterize the coordination of NEO1, MT2, HJV, ALK3 (an essential BMP receptor for
hepcidin expression), BMPs, TfR2, HFE, and transferrin in the regulation of hepcidin by iron. Our central
hypothesis is that hepatic NEO1 acts as a scaffold and a signaling receptor to facilitate the formation of a key
hepcidin-inducing complex. The MT2 suppression and iron induction of hepcidin are achieved by modulating
this NEO1-containing complex. This hypothesis has been formulated on the basis of the data produced by the
applicants' and other laboratories. The rationale for the proposed research is that understanding the regulation
of hepcidin expression by iron has the potential to develop new therapies for iron overload disorders and iron-
restricted anemia. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific
aims: 1) Determine the mechanism by which hepatic NEO1 acts as a scaffold and a signaling receptor to
induce hepcidin expression. 2) Test the hypothesis that MT2 suppression and iron induction of hepcidin
expression are orchestrated by hepatic NEO1. The approach is innovative, because it focuses on the
mechanistic studies of NEO1 and MT2 in iron-regulated hepcidin expression at molecular, cellular, and
systemic levels. The proposed research is significant, because it is expected to provide the basis for the
development of pharmacologic strategies. Successful completion of these studies will not only increase our
understanding of systemic iron homeostatic mechanism but also lay the foundation for translating these
advances into tangible benefits for patients with iron disorders.

## Key facts

- **NIH application ID:** 10978144
- **Project number:** 2R01DK102791-09
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** CAROLINE ENNS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,029
- **Award type:** 2
- **Project period:** 2015-02-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978144

## Citation

> US National Institutes of Health, RePORTER application 10978144, Roles of Neogenin and Matriptase-2 in Iron Homeostasis (2R01DK102791-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10978144. Licensed CC0.

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