Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway

Abstract

Rhomboid proteins perform a wide range of important functions in a variety of organisms. Recent studies have revealed that rhomboid proteins are involved in human cancer progression; however, the underlying molecular mechanism remains largely unclear. Here we show that RHBDD1, a rhomboid intramembrane serine protease, is highly expressed and closely associated with survival in patients with colorectal cancer. We observe that inactivation of RHBDD1 decreases tumor cell growth. Further studies show that RHBDD1 interacts with proTGFα and induces the ADAM-independent cleavage and secretion of proTGFα. The secreted TGFα further triggers the activation of the EGFR/Raf/MEK/ERK signalling pathway. Finally, the positive correlation of RHBDD1 expression with the EGFR/Raf/MEK/ERK signalling pathway is further corroborated in a murine model of colitis-associated colorectal cancer. These findings provide evidence of a growth-promoting role for RHBDD1 in colorectal cancer and may aid the development of tumor biomarkers or antitumor therapeutics.

Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

“…We find that RHBDL4 enhances ER-to-Golgi trafficking of the unprocessed, full-length TGFα but, contrary to a previous report16, does not directly contribute to its shedding. Unexpectedly, RHBDL4 regulates secretion of TGFα, and other cargoes, in extracellular microvesicles.…”

Intramembrane proteases as drug targets

“…endoplasmic reticulum (ER)-associated degradation [21]. Recently, it has been shown that upregulation of RHBDL4 is linked to poor prognosis in colorectal cancer and that inactivation (by genetic methods) led to a decrease in growth of colorectal cancer cell lines [22]. The authors of this study concluded that the phenotype occurred through RHBDL4-mediated cleavage of transforming growth factor alpha (TGFa).…”

Involvement of a conserved GFG motif region in substrate binding by RseP, an Escherichia coliS2P protease

“…Recent research revealed that these I-CLiPs play important roles in a variety of biological processes, including lipid homeostasis, EGF signaling, Notch signaling, stress response and bacterial sporulation and virulence (Nakayama et al, 2011;Kroos and Akiyama, 2013;Rawson, 2013;Schneider and Glickman, 2013;Lastun et al, 2016). I-CLiPs have been associated with several diseases such as Alzheimer's disease and Parkinson's disease (Walder et al, 2005;De Strooper et al, 2012;Song et al, 2015;Spinazzi and De Strooper, 2016).…”