# Role of iRhoms and ADAM17 in EGFR and TNFalpha signaling

> **NIH NIH R35** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $323,456

## Abstract

ADAM17 (a disintegrin and metalloprotease 17) is a cell surface metalloprotease with vital roles in
regulating the EGF-receptor as well as TNFa signaling. EGFR-ligands and TNFa are made as membrane-
anchored precursors that must be proteolytically released or “shed” to activate the soluble signaling molecule.
Mice lacking ADAM17 resemble mice lacking the EGFR, providing genetic evidence for the essential role of
ADAM17 in EGFR signaling. Moreover, inactivation of ADAM17 in myeloid cells protects from septic shock in
mice, which is caused by the release of soluble TNFa from myeloid cells. These functions establish ADAM17
as an important potential target for the treatment of EGFR- and TNFa-dependent pathologies such as cancer
and autoimmune diseases. ADAM17 activity is highly regulated and is influenced by numerous signaling
pathways. How these pathways functionally intersect with ADAM17 and how ADAM17 is activated are key
questions that are the main focus of my lab. Previously, we had found that ADAM17 is regulated by its
transmembrane domain (TMD), which ultimately led us to identify the seven-membrane spanning iRhoms1 and
2 (iR1, iR2) as novel regulators of ADAM17. We showed that iR2 controls the function of ADAM17 in immune
cells and that inactivation of iR1 and iR2 abolishes all functions of ADAM17 in mice, thereby providing
biochemical, cell biological and genetic evidence that iR1 and iR2 are the long sought-after regulators of
ADAM17. The main goals of the current proposal are to understand how iR1 and 2 integrate, interpret and
execute the signals that drive the activation of the ADAM17/EGFR- and ADAM17/TNFa signaling pathway.
 In the next 5 years, we will explore the biosynthesis and regulation of the iRhom/ADAM17 complexes and
how they target substrates in a selective manner. We know that the cytoplasmic domain of ADAM17 is
required to stabilize the protein, most likely so that it can assembly with an iRhom in the endoplasmic reticulum
(ER). We would like to identify the factors that stabilize ADAM17 and the sites in ADAM17 and the iRhoms
that promote their interaction. Once the iRhoms have assembled with ADAM17, they move to the cell surface.
We will use mutant iRhoms that are retained in the ER to identify binding partners that regulate their export
from the ER. We will also explore how the substrate selectivity of iRhoms is determined at the molecular level.
Finally, ADAM17 is unique in that it responds rapidly to several different signaling pathways, a property that is
thought to be essential for its role in skin and intestinal barrier protection. We will study the molecular details of
the on/off switch for ADAM17, and generate mice that express a constitutively active ADAM17 that cannot be
activated to determine how important this unique property of ADAM17 is in vivo.
 Together, our planned studies will resolve the most pressing current questions regarding the regulation of
ADAM17, a major cellular sheddase that is critical for TNFa...

## Key facts

- **NIH application ID:** 9851504
- **Project number:** 1R35GM134907-01
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Carl Peter Blobel
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,456
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851504

## Citation

> US National Institutes of Health, RePORTER application 9851504, Role of iRhoms and ADAM17 in EGFR and TNFalpha signaling (1R35GM134907-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9851504. Licensed CC0.

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