Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL.

ABSTRACT: Clostridium perfringens toxin TpeL belongs to the family of large clostridial glycosylating toxins. The toxin causes N-acetylglucosaminylation of Ras proteins at threonine35 thereby inactivating the small GTPases. Here, we show that all main types of oncogenic Ras proteins (H-Ras, K-Ras and N-Ras) are modified by the toxin in vitro and in vivo. Toxin-catalyzed modification of Ras was accompanied by inhibition of the MAP kinase pathway. Importantly, TpeL inhibited the paradoxical activation of the MAP kinase pathway induced by the BRAF inhibitor Vemurafenib in the human melanoma cell line SBCL2. The toxin also blocked Ras signaling in a zebrafish embryo model expressing oncogenic H-Ras^G12V, resulting in a reduction of melanocyte number. By using the binding a

SUBMITTER: Schorch B 

PROVIDER: S-EPMC5893256 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature