The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras.

Publication Type:

Featured

Source:

Molecular cell, Volume 45, Issue 5, p.610-8 (2012)

Keywords:

Adultdigestive disease, digestive deseases Ageddigestive disease, digestive deseases Aged, 80 and overdigestive disease, digestive deseases Animalsdigestive disease, digestive deseases Apoptosisdigestive disease, digestive deseases Binding Sitesdigestive disease, digestive deseases Binding, Competitivedigestive disease, digestive deseases Carcinoma, Hepatocellulardigestive disease, digestive deseases Cell Movementdigestive disease, digestive deseases Cell Transformation, Neoplasticdigestive disease, digestive deseases Genes, rasdigestive disease, digestive deseases HEK293 Cellsdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Intracellular Signaling Peptides and Proteinsdigestive disease, digestive deseases Liver Neoplasmsdigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred C57BLdigestive disease, digestive deseases Middle Ageddigestive disease, digestive deseases NIH 3T3 Cellsdigestive disease, digestive deseases Oncogene Protein v-aktdigestive disease, digestive deseases ral GTP-Binding Proteinsdigestive disease, digestive deseases ral Guanine Nucleotide Exchange Factor

Abstract:

The connection between cancer and inflammation is widely recognized, yet the underlying molecular mechanisms are poorly understood. We report here that TIPE2 provides a molecular bridge from inflammation to cancer by targeting the Ras signaling pathway. TIPE2 binds the Ras-interacting domain of the RalGDS family of proteins, which are essential effectors of activated Ras. This binding prevented Ras from forming an active complex, thereby inhibiting the activation of the downstream signaling molecules Ral and AKT. Consequently, TIPE2 deficiency led to heightened activation of Ral and AKT, resistance to cell death, increased migration, and dysregulation of exocyst complex formation. Conversely, TIPE2 overexpression induced cell death and significantly inhibited Ras-induced tumorigenesis in mice. Importantly, TIPE2 expression was either completely lost or significantly downregulated in human hepatic cancer. Thus, TIPE2 is an inhibitor of both inflammation and cancer, and a potential drug target for inflammatory and neoplastic diseases.