Inactive rhomboid protein 2 (RHBDF2)

Inactive rhomboid protein 2 (RHBDF2, iRhom2) is a catalytically inactive member of the rhomboid family of intramembrane serine proteases, distinguished by the absence of proteolytic activity but exhibiting essential regulatory functions. iRhom2 is a transmembrane protein that controls the maturation, trafficking, and activity of the metalloprotease ADAM17 (a disintegrin and metalloproteinase 17), which is responsible for the release (shedding) of a variety of signaling molecules, including TNF and ligands for the epidermal growth factor receptor (EGFR) such as amphiregulin and HB-EGF[1][2][3][4]. By modulating these pathways, iRhom2 influences inflammation, cell proliferation, tissue regeneration, and tumorigenesis. Mutations in RHBDF2 are associated with familial forms of esophageal cancer and palmoplantar keratoderma, highlighting the clinical relevance of this pseudoprotease. Though mainly investigated as a disease-associated modulator rather than a classical drug target, its regulatory involvement in major signaling pathways makes it a molecule of rising interest for therapeutic development, especially in cancer and inflammatory diseases.

Other names

iRhom2Rhomboid 5 homolog 2IRHOM2FLJ22341RHBDL5RHBDL6TOCTOCGRhomboid family member 2Rhomboid veinlet-like protein 5Rhomboid veinlet-like protein 6

Modulators or inhibitors would act by blocking iRhom2-dependent maturation and trafficking of ADAM17 or modulating EGFR ligand shedding to influence downstream pathways (not clinically established)