The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras.
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.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Yael
Y
Gus-Brautbar
Derek
D
Johnson
Li
L
Zhang
Honghong
H
Sun
Peng
P
Wang
Shirley
S
Zhang
Lining
L
Zhang
Youhai H
YH
Chen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D011905:Genes, ras; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D041681:NIH 3T3 Cells; D051058:Oncogene Protein v-akt / Q000235:genetics; D020725:ral GTP-Binding Proteins / Q000235:genetics; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C552057:TNFAIP8L2 protein, human; D020726:ral Guanine Nucleotide Exchange Factor; D051058:Oncogene Protein v-akt; D020725:ral GTP-Binding Proteins