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Updated: Aug 12, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth

Marina Badenes1,2,3, Emma Burbridge1,4, Ioanna Oikonomidi1

  • 1Instituto Gulbenkian de Ciência, Oeiras, Portugal.

Life Science Alliance
|January 31, 2023
PubMed

Insights

The FERM domain-containing protein iTAP/Frmd8 protects the metalloprotease ADAM17 from degradation. Loss of iTAP/Frmd8 impairs inflammatory repair and cancer growth, offering a targeted therapeutic approach for ADAM17-related diseases.

Area of Science:

  • Molecular and Cellular Biology
  • Biochemistry
  • Immunology

Background:

  • ADAM17 is a metalloprotease crucial for shedding TNF and EGF ligands, operating within a complex with iRhoms.
  • iTAP/Frmd8, an iRhom-binding protein, stabilizes ADAM17 and iRhom2 by preventing lysosomal degradation.

Purpose of the Study:

  • To investigate the pathophysiological roles of iTAP/Frmd8 by analyzing its impact on ADAM17-associated phenotypes in mice.
  • To explore the potential of iTAP/Frmd8 as a therapeutic target for inflammatory diseases and cancer.

Main Methods:

  • Generation and characterization of iTAP/Frmd8 knockout (KO) mice.
  • Assessment of inflammatory and intestinal epithelial barrier repair functions in iTAP/Frmd8 KO mice.
  • Evaluation of iTAP/Frmd8's role in cancer cell growth and the tumor microenvironment.

Main Results:

  • iTAP/Frmd8 KO mice displayed defects in inflammatory and intestinal epithelial barrier repair, distinct from global ADAM17 loss phenotypes.
  • iTAP/Frmd8 was found to regulate cancer cell proliferation both intrinsically and by influencing the tumor microenvironment.
  • Loss of iTAP/Frmd8 did not replicate the collateral defects observed with global ADAM17 deficiency.

Conclusions:

  • iTAP/Frmd8 plays a critical role in regulating ADAM17-mediated processes, particularly in inflammatory responses and epithelial repair.
  • Targeting iTAP/Frmd8 offers a promising strategy for modulating ADAM17 activity in specific contexts like chronic inflammation and cancer.
  • Pharmacological targeting of iTAP/Frmd8 could provide therapeutic benefits while mitigating the systemic side effects associated with broad ADAM17 inhibition.

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