Palmoplantar keratoderma-esophageal carcinoma syndrome

Rhomboids were first named after a mutation in the fruit fly Drosophila, discovered in a famous genetic screen that won Christiane Nüsslein-Volhard and Eric Wieschaus the Nobel Prize. In this screening, they found a number of mutants with similar phenotypes: "pointed" embryonic head skeletons, one of which was rhomboid. Hence the name "rhomboid".

Palmoplantar keratosis with esophageal cancer and mutation in RHBDF2, also known as TOC syndrome, is an autosomal dominant paraneoplastic syndrome characterized by ,callus-like palmoplantar keratosis localized to pressure points, oral leukoplakia, and a 95% lifetime risk of esophageal cancer.

Palmoplantar keratosis with esophageal carcinoma is due to a mutation in the RHBDF2 gene. The enzyme encoded by this gene is a (inactive) Drosophila rhomboid protease. Drosophila rhomboid proteases are positive regulators of EGF receptor(EGFR) signaling. RHBDF2 belongs to a conserved family of inhibitory rhomboid-like pseudoproteases that lack essential catalytic residues and inhibit rhomboid-dependent EGF signaling.

RHBDF2 is altered in tylotic skin compared to normal skin. Immortalized tylotic keratinocytes have lower levels of total epidermal growth factor receptor (EGFR) but show increased proliferation and migration potential compared to normal cells. It is likely that EGFR signaling is dysregulated in tylotic cells. Furthermore, the localization of RHBDF2 was shown to be disturbed in both tylotic and sporadic squamous cell tumors of the esophagus.

The rhomboid proteases are a family of enzymes found in almost all species. They are proteases: they cut the polypeptide chain of other proteins. This proteolytic cleavage is irreversible in cells and is an important type of cellular regulation. Although proteases are one of the oldest and best studied classes of enzymes, rhomboids belong to a recently discovered type of proteases: the intramembrane proteases.

Intramembrane proteases are unique in that their active sites are hidden in the lipid bilayer of cell membranes and they cleave other transmembrane proteins within their transmembrane domains. Approximately 30% of all proteins have transmembrane domains, and their regulated processing often has significant biological consequences. Accordingly, rhomboids regulate many important cellular processes and may be involved in a variety of human diseases.

For example, the protease function of rhomboids was discovered by showing that they regulate EGF receptor signaling in Drosophila. Furthermore, rhomboid-1 was shown to regulate sleep in Drosophila. Meanwhile, there is some evidence that rhomboids are involved in growth factor signaling in mammals, including humans. Mammalian rhomboid proteases have also been linked to ephrin signaling, cleavage of the anticoagulant protein thrombomodulin, and wound healing.

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