RHBDF2 Gene

The RHBDF2 gene (RHBDF2 stands for "Rhomboid 5 Homolog 2") is a protein-coding gene located on chromosome 17q25.1. It is 30,534 kilobases long and encodes a protein of 856 amino acids and a predicted molecular weight of 96,686 kilodaltons (rhomboid family member 2), an inactive rhomboid (iRhom) protease, iRhom2, which belongs to an enzyme family containing a long cytosolic N-terminus and a resting peptidase domain of unknown function. iRhom2 is associated with epithelial regeneration and cancer growth through constitutive activation of epidermal growth factor receptor (EGFR).Furthermore, the protein plays an important role in the secretion of tumor necrosis factor alpha (Adrain C et al. 2012). The encoded protein itself, is an inactive protease and thus does not exhibit protease activity. However, it exerts a role in sleep, cell survival, proliferation, migration and inflammation via control functions.

Diseases associated with RHBDF2 include:

• Keratosis palmoplantaris with esophageal carcinoma and mutation in RHBDF2 (TOC; Howel-Evans syndrome) (Blaydon DC et al. 2012).

The alternative name iRhom2 was proposed for the name "Rhomboid family member 2", this to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases

The rhomboids are a family of multitransmembrane proteins, many of which have been associated with tumor progression. Thus, disease progression in clear cell renal cell carcinoma is influenced by variations in the expression of rhomboid family genes. In particular, high levels of RHBDF2 gene expression are an indicator of poor prognosis in clear cell renal cell carcinoma. Patients with high RHBDF2 expression levels have poorer survival rates compared with those with low RHBDF2 levels. Silencing of the RHBDF2 gene results in significantly reduced cell proliferation and migration in tumor cell lines (Wang L et al. 2021).

1. Adrain C et al. (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335:225-228.
2. Blaydon DC et al (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet 90:340-346.

3. Hosur V et al (2014) Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proc Natl Acad Sci U S A 111:E2200-2209.

4. Lohi O et al (2004) Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by Mammalian rhomboids. Curr Biol 14:236-241.
5. Wang L et al (2021) RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression. Cancer Cell Int 21:590.